1. 1-Cytoskeletal components of the neurons and their functions during axon
regeneration.
Neurons contain a cytoskeleton consisting of neurofibrils, which determine the
shape of the soma and the various processes extending from it, and which transport
substances throught the neuron
Microtubules and microtubule associated proteins (MAP)
 25-28nm
 are narrow longitudinal tubes present in all neuronal processes. The
tubesmantain shape, and also transport molecules such as neuro-transmitters
from the soma to the axon terminals (anterograd transport), or from the terminals
to the soma (retrograde transport). There are at least two types of axonal
transport:
(a) rapid, 400nm
(b) slow, at less than 1 mm day
Microfilaments
 5-7 nm
 present in high concentrations as a meshwork beneath the membrane of the
axon. Actin is a important protein in axon development , and causes the
movement of the growth cone.
 Are a proliferation of globulin actin (G-actin) in the axolemma of the synapse,
depolarisation of the microfilaments is a prerequesite for releasing of the
trasmitters from the synapse vesicles.
Neurofilamets
 10nm
 Are the most abundant of the fibrillar elements in the neuron, and form the
bones of the cytoskeleton
 they are largely spaced, having tide arms that keep them appart and provide
neuronal stability
 seem to be invoolved in the transport mechanisms
3 different types of neurons:
1. unipolar
2. bipolar – concentrated mainly in periphery
3. multi-polar – formed by alfa and beta tubules
according to size:
1. Type I Golgi (large+long axons)
2. Type II Golgi (small+short axons)

2. 2-Types of axoplasmatic transports according direction and speed, their
functions in the intact neuron and during axon regeneration.
Axonal Transport: Various secretory products produced in the cell body are carried to the axon
terminals by special transport mechanism as in the same manner various constituents are carried
from the axon terminals to the cell body.
Three main types of axonal transport are:
⇒ fast anterograde transport
⇒ slow anterograde transport
⇒ fast retrograde transport.
Fast anterograde transport is involved in the transport of materials that have a
functional role at the nerve terminals (e.g., precursors of peptide neurotransmitters,
enzymes needed for the synthesis of small molecule neurotransmitters, and
glycoproteins needed for reconstitution of the plasma membrane) are trasported from
the cell body to the terminals. Polypeptides much larger than final peptide
neurotransmitters (pre-propeptides) and enzymes needed for the synthesis of small
molecule neurotransmitters are synthesized in the rough endoplasmic reticulum. The
vesicles formed in the Golgi apparatus for the axon terminals then become attached to
the microtubules and are transported by fast axonal transport (at a rate of 400 mm/d)
into the nerve terminal.
The rapid axonal transport depends on the microtubules. The microtubule
provides a stationary track and a microtubule-associated ATPase (kinesin) forms a
cross-bridge between the organelle to be moved and the microtubule. On one end,
kinesin contains two globular heads that bind to the microtubule, and on the other end, it
has a fan-shaped tail that binds to the surface of an organelle. The organelle then moves
by sliding of the kinesin molecule along the microtubule
Slow anterograde transport involves movement of neurofilaments and microtubules
synthesized in the cell body to the terminals at a rate of 5 mm/d. Soluble proteins
transported by this mechanism include actin, tubulin (which polymerizes to form
microtubules), proteins that make up neurofilaments, myosin, and a calcium-binding
protein (calmodulin).
Fast retrograde transport is slower than the fast anterograde transport (about 200 mm/
d). Rapid retrograde transport carries materials from the nerve terminals to the cell
body; the transported materials travel along microtubules.
An example of transport by this mechanism is nerve growth factor (NGF), a
peptide synthesized by a target cell and transported into certain neurons in order to
stimulate their growth. Materials lying outside the axon terminals are taken up by
endocytosis and transported to the cell body. Fast retrograde axonal transport is also
involved in some pathological conditions. For example, the herpes simplex, polio, and
rabies viruses and tetanus toxin are taken up by the axon terminals in peripheral nerves
and carried to their cell bodies in the central nervous system (CNS) by rapid retrograde
transport.

3. 3-Types of the neuronal synapses, their classification according morphology and
neurotransmitters.
Synapses needed for communication e.g.interneuronal synapses or intermuscular
Direct synapses in neuromuscular junction
Indirect synapses in autonomic postganglionic synapse
Synapses may be either:
1. interneuronal connections
2. connections between the neuron and effector
Interneuronal connections
according to position of connections:
- axodendritic and axo somatic synapses
- axo-axonal and dendro – dendritic synapses
according to effect on postsynaptic element
-excitatory synapses
-inhibitory synapses
according to transmission of the excitation
- eletric synapses: - reduced extracellular space
- transport of info by ionic flow
-continuity of cytoplasm
-chemical synapses: -presynaptic termination
- postsynaptic element
- active zone
- synaptic cleft – no continuity between pre and post-
synapses
-increased extracellular space

4. - transport of info by neurotransmitters
4-Glial cell types and their participation in the ontogenetic development of the
CNS
The supporting cells located in the CNS are called neuroglia or simply glial cells. They
are nonexcitable and more numerous (5 to 10 times) than neurons. Neuroglia have been
classified into the following groups: astrocytes, oligodendrocytes, microglia, and
ependymal cells.
⇒ Astrocytes
Among the glial cells, astrocytes are the largest and have a stellate (star-shaped)
appearance because their processes extend in all directions. Their nuclei are ovoid and
centrally located. The astrocytes provide support for the neurons, a barrier against the
spread of transmitters from synapses, and insulation to prevent electrical activity of one
neuron from affecting the activity of a neighboring neuron.
They are further subdivided into the following subgroups:
a) Protoplasmic Astrocytes: These cells are present in the gray matter in close
association with neurons. Because of their close association with the neurons, they are
considered satellite cells and serve as metabolic intermediaries for neurons. They give
out thicker and shorter processes, which branch profusely. Several of their processes
terminate in expansions called end-feet. Abutting of processes of protoplasmic
astrocytes on the capillaries as perivascular end-feet is one of the anatomical features of
the blood-brain barrier
b) Fibrous Astrocytes
These glial cells are found primarily in the white matter between nerve fibers. Several
thin, long, and smooth processes arise from the cell body; these processes show little
branching. Fibrous astrocytes function to repair damaged tissue, and this process may
result in scar formation.
c) MĂĽller Cells
These modified astrocytes are present in the retina.

5. ⇒ Oligodendrocytes
These cells are smaller than astrocytes and have fewer and shorter branches.
Their cytoplasm contains the usual organelles (e.g., ribosomes, mitochondria, and
microtubules), but they do not contain neurofilaments. In the white matter,
oligodendrocytes are located in rows along myelinated fibers and are known as
interfascicular oligodendrocytes. These oligodendrocytes are involved in the
myelination process. The oligodendrocytes present in the gray matter are called
perineural oligodendrocytes.
⇒ Microglia
These are the smallest of the glial cells. They usually have a few short branching
processes with thorn-like endings. These processes arising from the cell body give off
numerous spine-like projections. They are scattered throughout the nervous system.
When the CNS is injured, the microglia become enlarged, mobile, and phagocytic.
⇒ Ependymal Cells
Ependymal cells consist of three types of cells:
a) Ependymocytes are cuboidal or columnar cells that form a single layer of lining in
the brain ventricles and the central canal of the spinal cord. They possess microvilli and
cilia. The presence of microvilli indicates that these cells may have some absorptive
function. The movement of their cilia facilitates the flow of the cerebrospinal fluid.
b) Tanycytes are specialized ependymal cells that are found in the floor of the third
ventricle, and their processes extend into the brain tissue where they are juxtaposed to
blood vessels and neurons. Tanycytes have been implicated in the transport of hormones
from the CSF to capillaries of portal system and from hypothalamic neurons to the CSF.

6. c) Choroidal epithelial cells are modified ependymal cells. They are present in the
choroid plexus and are involved in the production and secretion of CSF. They have tight
junctions that prevent the CSF from spreading to the adjacent tissues
⇒ PNS
In the peripheral nervous system (PNS), Schwann cells provide myelin
sheaths around axons. The myelin sheaths are interrupted along the length of the
axons at regular intervals at the nodes of Ranvier. Thus, the nodes of Ranvier are
+
uninsulated and have a lower resistance. These nodes of Ranvier are rich in Na
channels, and the action potential becomes regenerated at these regions.
Therefore, the action potential traveling along the length of the axon jumps from
one node of Ranvier to another. This type of propagation enables the action
potential to conduct rapidly and is known as saltatory conduction. During the
myelination, the axon comes in contact with the Schwann cell, which then
rotates around the axon in clockwise or counterclockwise fashion. As the
Schwann cell wraps around the axon, the cytoplasm becomes progressively
reduced, and the inner layers of the plasma membrane come in contact and fuse
together.
⇒ CNS
Within the brain and the spinal cord, oligodendrocytes form the myelin sheaths
around axons of neurons. Several glial processes arise from one oligodendrocyte and
wrap around a portion of the axon. The intervals between adjacent oligodendrocytes are
devoid of myelin sheaths and are called the nodes of Ranvier. Unlike in peripheral
axons, the process of an oligodendrocyte does not rotate spirally on the axon. Instead, it
may wrap around the length of the axon. The cytoplasm is reduced progressively, and
the sheath consists of concentric layers of plasma membrane. Unlike in peripheral
nerves, one oligodendrocyte forms myelin sheaths around numerous (as many as 60)
axons of diverse origins.

7. 5-Glial cell types and their involvement in the ontogenetic development of the PNS.
 Glial cells of PNS originate from neural crest cells (plate)
 Schwmann cells produce myelin sheaths around myelinated axons of PNS neurons.
 Glial cells provide support as well as protection for neurons
 Most glial derived from ectodermal tissue (particularly neural tube and crest)
 The exception is microglia- derive from mesoderm .
 sattelite cells surrond neuronal cell bodies in PNS
 Schwmann cells of PNS promote regeneration of peripheral neurons
A myelinated nerve fiber is one that is surronded by a myelin sheath. In the CNS the
supporting cell is called oligodendrocytes, in the PNS is called Schmann cell.
The development of the myelin sheath provides an indication of the construction
of its lamellae. The body of Schmann cell forms a rolled up sheet of paper in which the
axon become embebedded. The structure develops, its margins become approximated
and eventually meet together, which results in duplication of the cell membrane – the
mesaxon (pair of parallel plasma membranes of a Schwann cell, marking the point of
edge-to-edge contact by the Schwann cell encircling the axon). This becomes spirally
bound around the axon, probably big movement of the Scwmann cell around the
enclosed axon. The beginning of the duplication lies on the inner side of the myelin
sheath (inner mesaxon) and its end on the outer side (outer mesaxon). Another type of
supporting cell are the satellite cells. Both Schwmann cellas and satellite cells develop
from neural crest cells.
Myelinating Schwann cells begin to form the myelin sheath in mammals during
fetal development and work by spiraling around the axon, sometimes with as many as
100 revolutions. A well-developed Schwann cell is shaped like a rolled-up sheet of
paper, with layers of myelin in between each coil. The inner layers of the wrapping,
which are predominantly membrane material, form the myelin sheath while the
outermost layer of nucleated cytoplasm forms the neurolemma. Only a small volume of
residual cytoplasm communicates the inner from the outer layers. This is seen
histologically as the Schmidt-Lantermann Incisure. Since each Schwann cell can cover

8. about a millimeter (0.04 inches) along the axon, hundreds and often thousands are
needed to completely cover an axon, which can sometimes span the length of a body.
6-Describe Wallerian degeneration and different reactions of the glial cells in
CNS and PNS following injury.
⇒ Neuronal Injury/ Injury of the Neuronal Cell Body
The neuronal cell body may be damaged by disease, ischemia (lack of blood
supply), or trauma.
In the CNS (the brain and spinal cord), the debris produced by neuronal damage
is phagocytosed by microglia. The adjacent fibrous astrocytes proliferate, and the
neurons are replaced by scar tissue.
In the PNS, macrophages are responsible for the removal of the debris produced
by neuronal damage, and the scar tissue is produced by the proliferation of the
fibroblasts.
Necrotic cell death is caused by acute traumatic injury that involves rapid lysis
of cell membranes. Necrotic cell death is different from apoptosis. Apoptosis is defined
as a genetically determined process of cell death and is characterized by shrinkage of
the cell, cellular fragmentation, and condensation of the chromatin. During the process
of formation of tissues from undifferentiated germinal cells in the embryo
(histogenesis), more neurons (about 2 times more) are formed than the neurons present
in the mature brain. The excess number of neurons is destroyed during the development
by apoptosis. The mechanism of apoptosis involves activation of a latent biochemical
pathway that is present in neurons and other cells of the body. The cellular debris after
neuronal cell death is removed by phagocytosis, which involves transport of solid
material into the cells (e.g., microglia) that remove the debris by indentation of the cell
membrane of the phagocyte and formation of a vesicle. Pinocytosis is similar to
phagocytosis, except that liquid material is removed. Exocytosis involves fusion of a
vesicle inside the nerve terminal (e.g., a vesicle containing a neurotransmitter) with the
plasma membrane and transportation of the contents of the vesicle outside the nerve
terminal.

9. ⇒ Axonal Damage/ Wallerian Degeneration
This type of degeneration refers to the changes that occur distally to the site of
damage on an axon. Because protein synthesis occurs primarily in the neuronal cell
body, the segment distal to the damaged site on the axon is affected profoundly.
Initially, the axon swells up and becomes irregular. Later, the axon and the terminal are
broken down into fragments that are phagocytosed by adjacent macrophages and
Schwann cells. Myelin is converted into fine drops of lipid material in the Schwann
cells and is extruded from these cells; it is removed by macrophages in the PNS and
microglial cells and invading macrophages in the CNS. Alterations may also be present
in the proximal segment of the axon up to the first node of Ranvier.
⇒ Chromatolysis
Sectioning of an axon may produce changes in the cell body, and if the injury is
close to the cell body, the neuron may degenerate. The cell body swells up due to edema
and becomes round in appearance, and the Nissl substance gets distributed throughout
the cytoplasm. The nucleus moves from its central position to the periphery due to
edema. The degenerative changes start within hours and are complete within a relatively
short time (about a week).
⇒ Anterograde Transneuronal Degeneration
This type of degeneration occurs in the CNS when damage to a neuron results in
the degeneration of another postsynaptic neuron closely associated with the same
function. For example, damage to an optic nerve results in the degeneration of the
lateral geniculate neurons receiving inputs from this nerve.
⇒ Retrograde Transneuronal Degeneration
This type of degeneration occurs in neurons sending inputs to an injured neuron.
In this situation, terminals of the neuron synapsing with a chromatolytic neuron
withdraw and are replaced by processes of glial cells. The neuron, from which the
inputs to the chromatolytic neuron arise, eventually degenerates.

10. ⇒ Recovery of Neuronal Injury (Regeneration)
If the damage to the neurons is not severe and they survive the injury,
regeneration is possible, but complete recovery may take as long as 3 to 6 months.
Within about 3 weeks, the swelling of the cell subsides, the nucleus occupies a central
position in the cell body again, and the Nissl bodies are normally distinguished. These
events indicate that protein synthesis has been restored in the neuronal cell body. In
severe damage, although sprouting occurs in axons in the CNS, this process ceases
within a short time (about 2 weeks). In this situation, normal functions of the neurons in
the CNS are not restored. However, in peripheral nerves, an axon can regenerate
satisfactorily if the endoneurial sheaths are intact. In this situation, the regenerating
axons reach the correct destination, and the chances of recovery of function are
reasonable. The growth rate of an axon has been estimated to be 2 to 4 mm per day.

11. 7-Describe developmental zones of the neural tube during histogenesis of the CNS, describe
cell populations originating from the neural crest.
The nervous system develops from ectoderm, the surface layer of embryonic
tissue. By the third to fourth week of embryonic development, the notochord, of
mesodermal origin, induces the development of the neural plate. By the third to fourth
week of embryonic development, there is a high rate of cell proliferation. As such, the
anterior part of the notochord (of mesodermal origin) begins to thicken, and thus, the
neural plate is formed by the third week of fetal life. The neural plate continues to
thicken over the following week and expands laterally. As it expands, the faster growing
lateral edges of the plate accumulate in a dorsal position as neural folds. As this plate
grows and widens, it forms a shallow groove along its longitudinal axis known as the
neural groove. The posterior end of the neural plate, which is narrower than the anterior
end, will ultimately become the spinal cord, whereas the broader, anterior end will
become the brain. As this plate grows and widens, the neural groove becomes deeper. In
the process of its forming and deepening, some of the cells located in the lateral margin
of the neural groove separate and migrate to a dorsal position to become the neural
crest. As the embryo grows, the neural folds fuse along the midline, thus forming a
neural tube.
The neural tube consists of three layers:
1. an inner layer called the ventricular layer, which is in contact with the cavity
of the neural tube;
2. an intermediate layer called the mantle layer; and
3. an outer layer called the marginal layer.
The ventricular zone is the major proliferative layer and also the first layer of the
forming neural tube to appear. The second layer to form is the marginal layer, followed
by the mantle layer. Early in development, the wall of the neural canal becomes
thickened, in part, by the formation of young or immature neurons that have yet to
completely differentiate (sometimes called neurocytes) in the mantle layer. Because this

12. layer contains the primary cell bodies of neurons, it will ultimately become the gray
matter of the spinal cord. Axons associated with cells in the mantle layer will grow into
the marginal layer.
Histogenesis of CNS:
1. Ventricular zone
-separates precursors for neurons and glial cells
− -migration of nuclei to base of ventricular cells
2. Marginal zone
− -no cell bodies
- axons of neurons from intermediate zone invade this zone
− 3. Intermediate zone
− - forms a interface of ventricular and intermediate zones
- no migration of nuclei
Cell populations originating from neural crest:
 During folding of neural crest, groups of cells appear along neural groove,
neural crest cells
 Some of these cells give rise sensory ganglia (dorsal root ganglia)
 cells of neural crest differentiate into Schwmann cells , pigment cells, meninges
and odontoblasts.

13. 8-Describe trophic interactions among the neurons and their target tissue, describe
general features of neurotrophic factors.
Trophism refers to the ability of certain molecules called trophic (nutritional)
factors, to promote cell survival. Neurotrophic factors are polypeptides that support
survival, growth, regeneration, and plasticity of neurons. Most types of neuron are
generated in excessive numbers, followed later by the death of “surplus” cells soon after
axons reach the vicinity of their target. This type of neuronal cell death is regarded to be
a consequence of the competition for the limited amount of neurotrophic factors
released by target cells (e, g., embryonic muscle cells). This is an adaptive means of
adjusting the number of neurons of each type to the number of target cells to be
innervated. The “trophic effect” exerted on neurons is illustrated by the trophic
influences of “taste nerve fibers” upon the taste buds. Not only do the gustatory
nerve fibers convey taste information, but they also have critical roles in both the
maintenance and regeneration of taste buds. Following transection of the gustatory
nerve fibers, the taste buds degenerate. In time, if and when the transected fibers
regenerate into the oral epithelium, new functional taste buds will differentiate from
epithelial cells, Presumably, only taste fibers elaborate the essential trophic factors to
induce the formation of new taste buds from the oral epithelium. Trophic activity could
occur at any time from embryonic life through adulthood. Although a progressive
reduction in activity occurs with age, it is never completely lost. In addition to trophic
effects, there are tropic effects. Tropism refers to the ability of certain molecules to
promote or to guide the outgrowth and directional growth or extension of neuronal
processes (axons and dendrites). Neurotrophins are a class among many neurotrophic
factors that have important roles in the survival of neurons and have widespread effects
throughout the CNS and peripheral nervous system (PNS). Neurotrophins include nerve
growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3),
and neurotrophin 4/5 (NT 4/5). Examples of related trophic factors include fibroblast
growth factor (FGF), the epidermal growth factor family (EGF) and cytokines. The
cytokines (e.g., interleukin, a leukemia-inhibitory factor) are extracellular or membrane-
anchored polypeptides that mediate communication between cells via cell surface

14. receptors. Trophic factors, as indicated, have roles in promoting the successive stages in
the cycle of neuronal differentiation, growth, survival, and programmed cell death
9-Selective neuronal death during ontogenic development of the nervous
system; describe a mechanism and its significance.
Programme cell death is an integral part of animal tissue development.
Development of an organ or tissue is often preceded by the extensive division and
differentiation of particular cell, with the resultant mass is then arranged in the correct
form with help of apoptosis.
Unlike cellular death (caused by hypoxia or other various injury), apoptosis
results in cell shrinkage and fragmentation. This allows the cells to be efficiently
phagocytosed and ther components removed without releasing of potentially harmful
intracellular substances into the surrounding tissue.
If a neuron (and especially its DNA) gets damaged by a virus or a toxin,
apoptosis destroys and silently removes these sick genes, which may serve to protect
surrounding healthy neurons. More importantly, apoptosis is a natural part of
development of the immature central nervous system. One of the many wonders of the
brain is the built-in redundancy of neurons early in development. These neurons
compete vigorously to migrate, innervate target neurons, and drink trophic factors
necessary to fuel this process. Apparently, there is survival of the fittest, because up to
50% of many types of neurons normally die in this time of brain maturation. Apoptosis
is a natural mechanism to eliminate the unwanted neurons without making as big a
molecular mess as doing it via necrosis.
Cell death via apoptosis is a prominent feature in mammalian neural
development. Recent studies into the basic mechanism of apoptosis have revealed
biochemical pathways that control and execute apoptosis in mammalian cells. Protein
factors in these pathways play important roles during development in regulating the
balance between neuronal life and death. Additionally, mounting evidence indicates
such pathways may also be activated during several neurodegenerative diseases,
resulting in improper loss of neurons.

15. 10-Describe molecular mechanisms for axon navigation to the target tissue during
development and regeneration of the nervous system.
Molecular mechanisms of axon guidance:
1. Contact inhibition – adhesion (permissive and non-permissive substrates)
2. Fasciculation (small, involuntary muscle contractions due to spontaneous
discharges)
3. Chemotropism (movement caused by chemical stimulus)
Cellular and molecular mechanisms for regeneration of nervous system:
Different reaction of the CNS and PNS neurons to injury of neural processes.
PNS neurons: anabolic processes due to increased synthesis of cytoskeleton and
membrane proteins and increased synthesis of RNA.
CNS neurons: reaction with distinct regressive mechanisms(atrophy) and destruction
of neurons. Decreased synthesis if the RNA

16. 11-Describe structural components of the hematoencephalic barrier, functional
significance of HEB.
 Meningeal barriers is formed by arachnoid placed between intradural blood
vessels and CSF in the subarachnoid space.
 Blood-brain barrier, which is located at the interface between the capillary
wall and brain tissue. The blood-brain barrier consists of:
(1) endothelial cells lining the capillary wall with tight junctions between them,
(2) processes of astrocytes abutting on the capillaries as perivascular end-feet,
(3) a capillary basement membrane.
This arrangement of different cells or their processes prevents the
passage of large molecules from the blood into the extracellular space between
the neurons and neuroglia and forms the anatomical basis of the blood-brain
barrier.
One of the beneficial functions of the blood-brain barrier is to prevent
entry of blood-borne foreign substances into the brain tissue. However, the
existence of this blood-brain barrier also presents a problem when the goal is to
deliver drugs into the CNS. In other organs, tight junctions do not exist between
the neighboring endothelial cells lining the capillaries.
 The capillaries and the ependymal epithelial cells of the choroid plexus form the
blood-CSF barrier between the blood and CSF. The presence of this barrier
results in distinct differences of concentration of some molecules in the blood
and CSF

17. 12-Describe the CNS liquid compartments and their barriers.
Fluid (liquid) compartments:
 Interstitial fluid: bathing neurons and glial cells within CNS
 CSF: in subarachnoid space and ventricular system.
 Blood: in the meningeal vessels
 Intracellular fluid: in neurons and glial cells
CSF: There are four main functions of the CSF. (1) The brain and spinal cord
float in the CSF because the specific gravities of these central nervous system (CNS)
structures are approximately the same. This buoyant effect of the CSF results in
reduction of traction exerted upon the nerves and blood vessels connected with the
CNS. (2) The CSF provides a cushioning effect on the CNS and dampens the effects of
trauma. (3) The CSF also serves as a vehicle for removal of metabolites from the CNS.
(4) Under normal conditions, the CSF provides a stable ionic environment for the CNS.
However, the chemical composition of the CSF may change in certain situations such as
administration of drugs that cross the blood-brain barrier.
The cerebral barriers:
 Meningeal barriers: is formed by arachnoid placed between intradural blood
vessels and CSF in the subarachnoid space

18. 13- Describe individual mechanisms of transportation throught the
hematoencephalic barrier.
Transport mechanisms of blood brain barrier (BBB)
⇒ Passive diffusion: lipid soluble substances pass throught the barrier, such as O2,
Co2, barbiturates, alcohol
⇒ Facilitated diffusion: substances that penetrate membranes by carrier or mediated
mechanisms. This category of transport carries more molecules and rapidly and
without consumption of enegy.
⇒ Active transport: consumption of energy, and uses carrier molecules. It proceeds
against a concentration gradient. E.g amino acids or extracellular potassium. Moves
molecules from the brain and CSF into blood plasma against a concentration
gradient.
⇒ Transcytosis: is selective transport by means of the coated vesicles that fuse to
form trasnsendothelial canal, e.g. Fe bind transferin ehich has Fe receptors
The combination of the specialized cell membrane of the endothelial cells linked
by intercellular tight junctions is the hallmark of the BBB. This duo effectively excludes
by blocking the passage of many substances across the capillary wall. The permeability
property can be enhanced by the state of phosphorylation of the proteins of the cell–cell
adherens junctions. The cadherin proteins of the adherens junctions also act as a sig-
nalling component between endothelial cells through linkages with the cytoskeletal pro-
tein filaments of the endothelial cells. The presence of so few pinocytotic vesicles with-
in the endothelial cells is indicative that the transcellular movement by vesicles across
the BBB (transendocytosis) is both relatively deficient and slow. However, the selective
passage of substances is related to the presence of high concentrations of carriermedi-
ated transport systems that act as transporters for glucose, essential amino acids, other
required nutrients, and macromolecules. These ensure the passage of essential sub-
stances from the blood to the CNSThe combination of the specialized cell membrane of
the endothelial cells linked by intercellular tight junctions is the hallmark of the BBB.
This duo effectively excludes by blocking the passage of many substances across the ca-
pillary wall. The permeability property can be enhanced by the state of phosphorylation
of the proteins of the cell–cell adherens junctions. The cadherin proteins of the adherens
junctions also act as a signalling component between endothelial cells through linkages
with the cytoskeletal protein filaments of the endothelial cells. The presence of so few
pinocytotic vesicles within the endothelial cells is indicative that the transcellular move-
ment by vesicles across the BBB

19. 14- Describe the CNS structures without total hematoencephalic barrier and their
function.
There are seven structures in the CNS that lack a blood-brain barrier. Called
circumventricular organs, they are the area postrema, pineal body, subcommissural
organ, subfornical organ, organum vasculosum of lamina terminalis (OVLT),
neurohypophysis (the posterior pituitary gland), and the median eminence.
They lack tight junctions in their capillaries. Instead, they have fenestrated
capillaries, capillary loops, and large perivascular spaces that permit the passage of
larger circulating molecules into the adjacent brain tissue. It is believed that some
circulating hormones consisting of large molecules reach their target areas in the brain
via the circumventricular organs. For example, the subfornical organ lies in the roof of
the third ventricle. Blood-borne angiotensin II reaches the subfornical organ readily
because of the lack of the blood-brain barrier in this organ and induces thirst for overall
regulation of fluid balance and cardiovascular homeostasis.
Functional effects
⇒ Acts as homeostatic organs: e.g neurohypophyses releases oxitocin and vasopressin
(ADH)
⇒ Acts as as chemoreceptors e.g. Angiotensin II may act to increase blood pressure
⇒ Acts as osmoreceptors
⇒ The area postrema is the vomiting centre of the brain, detect noxious substances in
the blood and stimulate vomiting in order to rid that substances from the body

20. 15- Measuring of the cerebral blood flow
The metabolic demands of the brain must be met with the blood supply to this
organ. Normal cerebral blood flow is about 50 mL/100 g of brain tissue/min. Thus, a
brain of average weight (1500 g) has a normal blood flow of 750 mL/min. Even a brief
interruption of the blood supply to the CNS may result in serious neurological
disturbances. A blood flow of 25 mL/100 g of brain tissue/min constitutes ischemic
penumbra (a dangerously deficient blood supply leading to loss of brain cells). A blood
flow of 8 mL/100 g of brain tissue/min leads to an almost complete loss of functional
neurons. Consciousness is lost within 10 seconds of the cessation of blood supply to the
brain.
Freks principle:
Cerebral blood flow can be measured by determining the amount of nitrous
oxide removed from the blood stream (Qx) per unit of time and dividing that value by
the difference between the concentration in the atrial blood (Ax) and the in the venous
blood (Vx):
Qx
CBF= ---------------
[Ax] - [Vx]
Qx= amount of nitrous oxide removed from the blood
Ax= concentration in atrial blood
Vx= concentration in the venous blood
Average blood flow in young adults is 54ml/100g/min
Average brain weight 1400g hence we have a blood flow to brain corresponding to
756ml/min
Factors that affect cerebral blood flow :
1) Intracranial pressure
2) Blood viscosity
3) Mean venous pressure
4) Mean atrial pressure
5) Constriction and dilation of cerebral arterioles

21. 16 – Blood flow in various parts of the brain Arterial supply of the brain:
Blood supply to the brain is derived from two arteries: (1) the internal carotid
artery and (2) the vertebral artery. These arteries and their branches arise in pairs that
supply blood to both sides of the brain. The basilar artery is a single artery located in the
midline on the ventral side of the brain. The branches of the basilar artery also arise in
pairs.
Internal Carotid Artery
This artery arises from the common carotid artery on each side at the level of the
thyroid cartilage and enters the cranial cavity through the carotid canal.
Branches:
⇒ The Ophthalmic Artery: enters the orbit through the optic foramen and gives rise
to the central artery of the retina, which supplies the retina and cranial dura.
Interruption of blood flow in the ophthalmic artery causes loss of vision in the
ipsilateral eye.
⇒ The Posterior Communicating Artery: arises at the level of the optic chiasm and
travels posteriorly to join the posterior cerebral arteries. Small branches arising
from this artery supply blood to the hypophysis, infundibulum, parts of the
hypothalamus, thalamus, and hippocampus.
⇒ The Anterior Choroidal Artery: arises near the optic chiasm and supplies the
choroid plexus located in the inferior horn of the lateral ventricle, the optic tract,
parts of the internal capsule, hippocampal formation, globus pallidus, and lateral
portions of the thalamus.
⇒ The Anterior Cerebral Artery: The anterior cerebral artery travels rostrally
through the interhemispheric fissure. It supplies blood to the medial aspect of the
cerebral hemisphere, including parts of the frontal and parietal lobes. This artery
also supplies blood to the postcentral gyrus and precentral gyrus. Occlusion of one
of the anterior cerebral arteries results in loss of motor control (paralysis) and loss
of sensation in the contralateral leg. Other structures supplied by the anterior
cerebral artery include the olfactory bulb and tract, anterior hypothalamus, parts of
caudate nucleus, internal capsule, putamen, and septal nuclei.
⇒ The Anterior Communicating Artery: at the level of the optic chiasm, the
anterior communicating artery connects the anterior cerebral arteries on the two
sides. A group of small arteries arising from the anterior communicating and
anterior cerebral arteries penetrates the brain tissue almost perpendicularly and
supplies blood to the anterior hypothalamus, including preoptic and suprachiasmatic
areas.
⇒ The Medial Striate Artery (Recurrent Artery of Heubner): arises from the
anterior cerebral artery at the level of the optic chiasm and supplies blood to the
anteromedial part of the head of the caudate nucleus and parts of the internal
capsule, putamen, and septal nuclei. The medial striate and the lenticulostriate
arteries penetrate the perforated substance.
⇒ The Middle Cerebral Artery: at the level just lateral to the optic chiasm. Branches
of the middle cerebral artery supply blood to the lateral convexity of the cerebral
hemisphere including parts of the temporal, frontal, parietal, and occipital lobes.

22. Vertebro-Basilar Circulation:
This system includes the two vertebral arteries, the basilar artery (which is formed by
the union of the two vertebral arteries), and their branches. This arterial system supplies
the medulla, pons, mesencephalon, and cerebellum. Braches:
⇒ The vertebral artery: on each side is the first branch arising from the subclavian
artery. It enters the transverse foramen of the sixth cervical vertebrae, ascends
through these foramina in higher vertebra, and eventually enters the cranium
through the foramen magnum. In the cranium, at the medullary level, each vertebral
artery gives off the anterior spinal artery, the posterior inferior cerebellar artery, and
the posterior spinal artery.
⇒ The Anterior Spinal Artery: at the confluence of the two vertebral arteries, two
small branches arise and join to form a single anterior spinal artery. This artery
supplies the medial structures of the medulla, which include the pyramids, medial
lemniscus, medial longitudinal fasciculus, hypoglossal nucleus, and the inferior
olivary nucleus.
⇒ The Posterior Inferior Cerebellar Artery (PICA): arises from the vertebral artery
and supplies the regions of the lateral medulla that include the spinothalamic tract,
dorsal and ventral spinocerebellar tracts, descending sympathetic tract, descending
tract of cranial nerve V, and nucleus ambiguus.
⇒ The Posterior Spinal Artery (PSA): It is the first branch of the vertebral artery in
the cranium in about 25% of cases. However, in a majority of cases (75%), it arises
from the posterior inferior cerebellar artery. In the caudal medulla, this artery
supplies the fasciculus gracilis and cuneatus as well as the gracile and cuneate
nuclei, spinal trigeminal nucleus, dorsal and caudal portions of the inferior
cerebellar peduncle, and portions of the solitary tract and dorsal motor nucleus of
the vagus nerve.
⇒ The Basilar Artery: The two vertebral arteries join at the caudal border of the pons
to form the single basilar artery.
⇒ The Anterior Inferior Cerebellar Artery (AICA): is the most caudal branch
arising from the basilar artery. The AICA supplies the ventral and inferior surface
of the cerebellum and lateral parts of the pons.
⇒ The labyrinthine (internal auditory) artery: is usually a branch of the AICA and
supplies the cochlea and labyrinth.
⇒ The Pontine Arteries: Several pairs of pontine arteries arise from the basilar
artery. Some pontine arteries (the paramedian arteries) enter the pons immediately
and supply the medial portion of the lower and upper pons. Some pontine arteries
(the short circumferential arteries) travel a short distance around the pons and
supply substantia nigra and lateral portions of the midbrain tegmentum.
⇒ The superior cerebellar artery: arises just caudal to the bifurcation of the basilar
artery and supplies the rostral level of the pons, caudal part of the midbrain, and
superior surface of the cerebellum.
⇒ The posterior cerebral arteries arise at the terminal bifurcation of the
basilar artery. Branches of the posterior cerebral arteries supply most of the
midbrain, thalamus, and subthalamic nucleus.
Cerebral Arterial Circle (Circle of Willis)

23. The cerebral arterial circle surrounds the optic chiasm and the infundibulum of the
pituitary. It is formed by the anastomosis of the branches of the internal carotid artery
and the terminal branches of the basilar artery. The anterior communicating artery
connects the two anterior cerebral arteries, thus forming a semicircle. The circle is
completed as the posterior communicating arteries arising from the internal carotid
arteries at the level of the optic chiasm travel posteriorly to join the posterior cerebral
arteries that are formed by the bifurcation of the basilar artery. The circle of Willis is
patent in only 20% of individuals. When it is patent, this arterial system supplies the
hypothalamus, hypophysis, infundibulum, thalamus, caudate nucleus, putamen, internal
capsule, globus pallidus, choroid plexus (lateral ventricles), and temporal lobe.

24. 17- Regulation of cerebral circulation. Brain metabolism.
Brain metabolism:
3 metabolic factors have potent effect on control of cerebral blood flow (CBF) :
⇒ Increase in [CO2] leads to increase of CBF.
CO2 + H2O  H2CO3  HCO3- + H+ AND the H+ causes the dilation of
cerebral vessels
⇒ Increase in H+ leads to increase in CBF
⇒ Decrease in O2 leads increase CBF via vasodilation
The brain (2% of the total body weight) receives about 15% of the cardiac output and
consumes about 20% of the total O2 consumption.
The brain is highly sensitive to disturbances of the blood supply. Ischaemia lasting
seconds causes symptoms and lasting for few minutes causes irreversible damage.
The caliber of the arterioles is regulated by:
⇒ Local vasodilators; metabolites (e.g. CO2)~
⇒ Vasoactive substances produced by the endothelium, circulating peptides such as
angiotensin II
⇒ Vasomotor nerves
⇒ Autoregulation mechanisms (the systemic blood pressure increases, but the cerebral
blood flow remains constant by:
a) intraluminar pressure within the arterioles elicits direct myogenic
responde
b) hypocapnia causes arterial vasoconstriction
Intracranial pressure:
⇒ cerebral vessels are compressed even if there is no increase in intracranial pressure
⇒ any change in venous pressure causes a similar change in intracranial pressure. A
rise in venous pressure decreases cerebral blood flow.
⇒ Cerebreal circulation has strong sympathetic innervation extending from the
superior cervical ganglion
⇒ Brain extremely sensitive to hypoxia
⇒ Ammonia very toxic to nerve cells and leaves the brain in the form of glutamine

25. 18- Formation and absorption of cerebrospinal fluid. Function of cerebrospinal
fluid.
Formation of the Cerebrospinal fluid:
About 70% of the CSF present in the brain and spinal cord is produced by the
choroid plexuses. The remaining 30% of CSF, which is secreted by the parenchyma of
the brain, crosses the ependyma (a single layer of ciliated columnar epithelial cells
lining the ventricular system) and enters the ventricles. The formation of CSF is an
active process involving the enzyme carbonic anhydrase and specific transport
mechanisms.
The formation of the CSF first involves filtration of the blood through the
fenestrations of the endothelial cells that line the choroidal capillaries. However, the
movement of peptides, proteins, and other larger molecules from this filtrate into the
CSF is prevented by the tight junctions that exist in the neighboring epithelial cells that
form the outer layer of the choroid plexus. Energy-dependent active transport
mechanisms are present in the choroidal epithelium for transporting Na+ and Mg2+ ions
into the CSF and for removing K+ and Ca2+ ions from the CSF. Water flows across the
epithelium for maintaining the osmotic balance. Normally, the rate of formation of CSF
is about 500 mL/day and the total volume of CSF is 90 to 140 mL, of which about 23
mL is in the ventricles, and the remaining is in the subarachnoid space.
Circulation:
The movement of CSF is pulsatile. It flows from the lateral ventricles into the
third ventricle through the foramina of Monro where it mixes with more CSF. Then, it
flows through the cerebral aqueduct (aqueduct of Sylvius) into the fourth ventricle,
where additional CSF is secreted. The fluid leaves the ventricular system via the
foramina of Luschka and Magendie and enters the cerebellomedullary cistern (cisterna
magna). The CSF then travels rostrally over the cerebral hemisphere where it enters the
arachnoid villi.
Absorption: is made throught the arachidonic vili. The CSF drains into dural
venous sinuses, there are valves here, so fluid flows only from vili to veins where
pressure difference is appropriate.
Functions:
There are four main functions of the CSF.
(1) The brain and spinal cord float in the CSF because the specific gravities of
these central nervous system (CNS) structures are approximately the same. This
buoyant effect of the CSF results in reduction of traction exerted upon the nerves and
blood vessels connected with the CNS.
(2) The CSF provides a cushioning effect on the CNS and dampens the effects of
trauma. (3) The CSF also serves as a vehicle for removal of metabolites from the CNS.
(4) Under normal conditions, the CSF provides a stable ionic environment for
the CNS.
Composition:
Normally, very little protein is present in the CSF, and this is the primary difference
between CSF and blood serum. The concentrations of glucose, as well as

26. 19 – Resting potential of the neuron
Resting membrane potential: When a neuron is not generating action
potentials, it is at rest. When the neuron is at rest, its cytosol along the inner surface of
its membrane is negatively charged compared with the charge on the outside. Typically,
the resting membrane potential (or resting potential) of a neuron is -65 millivolts (mV).
The potential difference across the cell membrane during resting state is called
the resting membrane potential. The lipid bilayer of the neuronal membrane maintains
this separation of charges by acting as a barrier to the diffusion of ions across the
membrane. The ion concentration gradients across the neuronal membrane are
established by ion pumps that actively move ions into or out of neurons against their
concentration gradients. The selective permeability of membranes is due to the presence
of ion channels that allow some ions to cross the membrane in the direction of their
concentration gradients. The ion pumps and ion channels work against each other in this
manner. If the neuronal membrane is selectively permeable to only a K+ ion, this ion
will move out of the neuron down its concentration gradient. Therefore, more positive
charges accumulate outside the neuron. The fixed negative charges inside the neuron
impede the efflux of positively charged K+ ions, and excess positive charges outside the
neuron tend to promote influx of the K+ ions into the neuron due to the electrostatic
forces. The opposite charges attract, while similar charges repel each other. Thus, two
forces are acting on the flow of K+ ions out of the neuron; a higher concentration inside
the neuron (concentration gradient) tends to expel them out of the neuron, while the
electrostatic forces tend to prevent their flow out of the neuron.
When the two opposing forces are equal, K+ concentrations inside and outside
the neuron are in equilibrium. The value of the membrane potential at this time is called
the K+ equilibrium potential. Thus, if the neuronal membrane contained only K+
channels, the resting membrane potential would be determined by the K+ concentration
gradient and would be equal to the equilibrium potential for K+ ions (approximately -80
mV). However, as stated earlier, the resting membrane potential of a neuron is usually
-65 mV. This is because neurons at rest are permeable to the Na+ ion also. The Na+ ions
tend to flow into the neuron due to two forces: (1) concentration gradient of Na+ ions
(extracellular Na+ concentration is much higher than its intracellular concentration) and
(2) electrostatic forces (there is an excess of positive charges outside and an excess of
negative charges inside the neuron). Due to the influx of Na+ ions, the resting membrane
potential deviates from that of the K+ equilibrium potential (i.e., it becomes -65 mV
instead of -80 mV).
However, the membrane potential does not reach the equilibrium potential for
+
Na . The reason for the neuron's inability to attain a resting membrane potential closer
to the Na+ equilibrium potential is that the number of open nongated Na+ channels is
much smaller than the number of open nongated K+ channels in the resting state of a
neuron. The permeability of Na+ is small despite large electrostatic and concentration
gradient forces tending to drive it into the neuron. To maintain a steady resting
membrane potential, the separation of charges across the neuronal membrane must be
maintained at a constant. This is accomplished by the Na+-K+ pump described earlier.
Goldman equation: since the neuronal membrane is permeable to more than
one ion, the goldman equation is used to calculate membrane potential. This equation
takes into account the contribution of the permeability of each ion and its extra- and
intracellular concentration.
Nerst equation: is used to calculate equilibrium potential of an ion that is
present on both sides of the cell membrane.

27. 20- Receptor, synaptic and action potential-description
Receptor potential: whatever the stimulus that excites the receptor, its immediate
effect is to arrange the membrane potential of the receptor. This change is called
receptor potential.
Different receptors can be excited, either:
a) By mechanical deformation that stretches the receptor membrane and
opens ion channels.
b) By application of a chemical to the membrane
c) By change of temperature
d) By eletromagnetic radiation
When the receptor potential rises above the threshold for eliciting an action potential,
the the action potential begins to appear. The more the receptor potential rises above the
threshold level, the greater becomes the action potential frequency
Synaptic potential: an interaction of a transmitter on postsynaptic neuron initiates a
synaptic potential.
Can be either: EPSP (excitatory postsynaptic potential)
IPSP (inhibitory postsynaptic potential)
Action potential: rapid change in the membrane potential. It begins with a sudden
change from the normal resting membrane potential to a positive membrane potential.
When a neuron receives an excitatory input, the neuronal membrane is
depolarized, resulting in an opening of some voltage-gated Na+ channels and influx of
Na+ . The accumulation of positive charges due to influx of Na+ promotes depolarization
of the neuronal membrane. When the membrane potential reaches threshold potential,
the chances of generating an action potential are about 50%. However, when the
membrane is depolarized beyond the threshold potential, a sufficient number of voltage-
gated Na+ channels open, relative permeability of Na+ ions is greater than that of K+
ions, and action potentials are generated with certainty.
During the rising phase of the action potential, there is a rapid depolarization of
the membrane due to increased permeability of Na+. The depolarization continues so
that the membrane potential approaches the Na+ equilibrium potential. The part of the
action potential where the inside of the neuron is positive relative to the outside is called
the overshoot. Towards the end of the rising phase of the action potential, voltage-gated
Na+ channels are inactivated, and the influx of Na+ through these channels is stopped.
During the falling phase of the action potential, the neuron is repolarized by opening of
voltage-gated K+ channels, which allows increased efflux of K+ from the neuron through
these channels. The opening of voltage-gated K+ channels is also caused by
depolarization of the neuronal membrane. Because these voltage-gated K+ channels
open with a delay (about 1 msec) after the membrane depolarization and their opening
rectifies the membrane potential, they are called delayed rectifier K+ channels. At the
end of the falling phase, the membrane potential is more negative than the resting
potential because of increased K+ permeability caused by the opening of the delayed
rectifier K+ channels in addition to the already present resting K+ permeability through
nongated channels. The permeability is closer to the equilibrium potential of K+ because
there is little Na+ permeability during this period. This portion of the action potential is
called after-hyperpolarization or undershoot. Once after-hyperpolarization has occurred,
the resting membrane potential is restored gradually as the voltage-gated K+ channels
close again.

28. 21 – Ionic basis of membrane potential changes
The resting membrane potential of a neuron is usually -65 mV. At rest, Na+
influx into the neuron through open nongated Na+ channels is balanced by the efflux of
K+ through open nongated K+ channels. Thus, the membrane potential remains constant
closer (but not equal) to the K+ equilibrium.
When a neuron receives an excitatory input, the neuronal membrane is
depolarized, resulting in an opening of some voltage-gated Na+ channels and influx of
Na+. Na+ channels are normally closed. The accumulation of positive charges due to
influx of Na+ promotes depolarization of the neuronal membrane. When the membrane
potential reaches threshold potential, the chances of generating an action potential are
about 50%. However, when the membrane is depolarized beyond the threshold
potential, a sufficient number of voltage-gated Na+ channels open, relative permeability
of Na+ ions is greater than that of K+ ions, and action potentials are generated with
certainty. Generation of an action potential is an all-or-nothing phenomenon. Because
the concentration of Na+ channels is relatively high at the axon hillock, this is the site of
generation of action potentials in a neuron.
During the rising phase of the action potential generation, there is a rapid
depolarization of the membrane due to increased permeability of Na+. The
depolarization continues so that the membrane potential approaches the Na+ equilibrium
potential. The part of the action potential where the inside of the neuron is positive
relative to the outside is called the overshoot. Towards the end of the rising phase of the
action potential, voltage-gated Na+ channels are inactivated, and the influx of Na+
through these channels is stopped.
During the falling phase of the action potential, the neuron is repolarized by opening of
voltage-gated K+ channels, which allows increased efflux of K+ from the neuron through
these channels. The opening of voltage-gated K+ channels is also caused by
depolarization of the neuronal membrane. Because these voltage-gated K+ channels
open with a delay (about 1 msec) after the membrane depolarization and their opening
rectifies the membrane potential, they are called delayed rectifier K+ channels. At the
end of the falling phase, the membrane potential is more negative than the resting
potential because of increased K+ permeability caused by the opening of the delayed
rectifier K+ channels in addition to the already present resting K+ permeability through
nongated channels. The permeability is closer to the equilibrium potential of K+ because
there is little Na+ permeability during this period. This portion of the action potential is
called after-hyperpolarization or undershoot. Once after-hyperpolarization has occurred,
the resting membrane potential is restored gradually as the voltage-gated K+ channels
close again.
The sodium channel exists in the following three states: resting, activated, or
inactivated.
• Resting state: During this state, the activation gate closes the channel pore
while the inactivation gate is open. With the channel pore closed, Na+ cannot
flow into the neuron.
• Activated state: During the rising phase of action potential, both activation and
inactivation gates are open, and Na+ ions flow into the neuron.
• Inactivated state: During this state, the inactivation gate closes the channel
pore while the activation gate is still open. Even though the activation gate is
open, Na+ cannot flow into the neuron. The neuron cannot be activated until the

29. 22- Ion channels in neurons – their distributions
Ion Channels:
. Ion channels are made up of proteins that are embedded in the lipid bilayer of
the neuronal membrane across which they span. They are characterized by the following
general properties.
• The flow of ions through the channels does not require metabolic energy; the
flow is passive.
• The electrochemical driving force across the membrane, but not the channel
itself, determines the direction and eventual equilibrium of this flow.
• The ionic charge determines whether a channel allows an ion to flow through;
some channels allow cations while others allow anions to flow through them.
• Most cation-selective channels allow only one ion species (e.g., Na+ or K+ or
Ca2+) to flow through them. However, some channels allow more than one ion
species to flow through them. For example, when L-glutamate (an excitatory
amino acid neurotransmitter) activates an N-methyl-D-aspartic acid (NMDA)
receptor, both Na+ and Ca2+ ions flow through the NMDA receptor channel into
the neuron.
• Most anion-selective channels allow only Cl- to flow through them.
• Some blockers can prevent the flow of ions through the ion channels. For
example, phencyclidine (PCP, or Angel Dust) blocks the NMDA receptor
channel.
Classification of Ion Channels:
Nongated Channels:
Although nongated channels are capable of opening as well as closing, most of the
time they are in the open site. They control the flow of ions during the resting
membrane potential. Examples include nongated Na+ and K+ channels that contribute to
the resting membrane potential.
Gated Channels:
These channels are also capable of opening as well as closing. All gated channels
are allosteric proteins
The channels that are opened or closed by a change in the membrane potential are
called voltage-gated channels. The opening and closing of the channel is believed to be
due to the movement of the charged region of the channel back and forth through the
electrical field of the membrane.
Voltage-gated channels exist in three states:
(1) resting state (the channel is closed but can be activated)
(2) active state (the channel is open), and
(3) refractory state (the channel is inactivated).
Changes in the electrical potential difference across the membrane provide the
energy for gating in these channels. Genes encoding for voltage-gated Na+, K+, and Ca2+
channels belong to one family. These channels are described as follows.
The voltage-gated Na+ channel is formed by a single long polypeptide (a string of
amino acids containing peptide bonds) that has four domains (I-IV). Each domain has
six hydrophobic alpha helices (S1aS6) that span back and forth within the cell
membrane. The four domains join together and form an aqueous pore of the channel.
An additional hydrophobic region connects the S5 and S6 alpha helical segments,

30. forming a pore loop. The presence of this pore loop makes the channel more permeable
to Na+ than to K+. The membrane-spanning S4 alpha helical segment is believed to be
voltage sensitive. At the resting membrane potential, the channel pore is closed. The S4
segment undergoes a conformational change when the membrane potential changes
(e.g., when the neuron is depolarized), the S4 segment is pushed away from the inner
side of the membrane, and the channel gate opens, allowing an influx of Na + ions. There
are some cases where Na+ permeability is blocked. Tetrodotoxin (TTX), a toxin isolated
from the ovaries of Japanese puffer fish, binds to the sodium channel on the outside and
blocks the sodium permeability pore. Consequently, neurons are not able to generate
action potentials after the application of TTX. These channels are also blocked by local
anesthetic drugs (e.g., lidocaine).
The basic structure of the voltage-gated Ca2+ channel is similar to that of the
voltage-gated Na+ channel. Ca2+ ions enter the postsynaptic neurons through these
channels and activate enzymes. Depolarization of presynaptic nerve terminals results in
entry of Ca2+ ions into the terminal via these channels. An increase in the levels of
intracellular Ca2+ results in the release of transmitters from presynaptic nerve terminals.
Different varieties of voltage-gated K+ channels have been identified, and they serve
different functions. The general scheme describing the components of this channel is
similar to that of the voltage-gated Na+ channel, except that the voltage-gated K+
channel consists of four polypeptides. It should be recalled that each polypeptide
contributing to the formation of a large protein molecule is called a subunit. Each
subunit of a voltage-gated K+ channel consists of six alpha-helical membrane-spanning
segments (S1 a S6). A pore loop makes the channel more permeable to K + than to Na+.
The S4 segment acts as an activation gate. The K+ channels are generally blocked by
chemicals such as tetraethylammonium (TEA) or 4-aminopyridine.
The ligand-gated channels are opened by noncovalent binding of chemical
substances with their receptors on the neuronal membrane. These chemical substances
include:
(1) transmitters or hormones present in the extracellular fluid that bind to their
receptors on the extracellular side of the channel and bring about a conformational
change to open the channel (e.g., acetylcholine, γ-aminobutyric acid [GABA], or
glycine); and
(2) an intracellular second messenger (e.g., cyclic adenosine monophosphate,
which is activated by a transmitter such as norepinephrine). The second messenger can
open the channel (1) directly by binding to the channel and causing a conformational
change or (2) indirectly by phosphorylating the channel protein in the presence of a
protein kinase and causing a conformational change; this effect on the channel is
reversed by dephosphorylation catalyzed by a protein phosphatase. Genes encoding for
transmitter-gated channels (e.g., channels activated by acetylcholine, GABA, or
glycine) and genes encoding for voltage-gated channels belong to different families.
Mechanically gated channels open by a mechanical stimulus and include the channels
involved in producing generator potentials of stretch and touch receptors.
23 – Spreading of membrane potentials. Length and time constant of the
membrane.
An action potential elicited at any one point on an excitable membrane usually
excites adjacent portions of the membrane, resulting in the propagation of the action
potential.

31. A nerve fiber excited at its midportion-develop increased permeability to Na+.
Positive electrical charges carried by the inward diffusing Na+ flow inside the fiber
throught depolarized membrane and then for several milimiters along the core of the
axon. These positive cgarges increase the voltage to above the thereshold. Thus the
depolarization process travels along the entire extent of the fiber and the transmission of
this depolarization process is called nerve impulse. The action potential will travel in
both directions away from the stimulus until the entire membrane becomes depolarized.
Once an action potential has been elicited at any point on the membtrane of a
normal fiber, the depolarization process travels over the entire membrane if conditions
are right, or it does not travel at all if conditions are not right- this is called “all or
nothing principle”, and it applies to all normal excitable tissues. Occasionally, the action
potential reaches a point on the membrane at which it does not generate voltage to
stimulate the next area of the membrane. When this occurs, the spread of depolarization
stops. Therefore, for continued propagation of an impulse , the ratio of action potential
to threshold for excitation must at all times be greater than 1 – safety factor for
propagation.
Length-constant: measures the effectiveness of neuron in longitudinal signal
transduction.
Rm
λ= √ -------------------
(Ri + Ro )
SOFIA: lambda e igual a raiz quadrada de abrir parentesis Rm sobre abrir
parentesis ( Ri + Ro )
Rm: is the resistance across the membrane
Ri: resistance inside the membrane
Ro: is the resistance outside the membrane
The larger the length constant the bigger the effect of the action potential
Long leght constant results in spatial summation
Time constant:
T= Rm . Cm
R: resistance
C: capacitance
Long-time constant results in temporal summation
24 – Temporal summation of membrane potentials.
Temporal summation: is an effect generated by a single neuron as a way of
achieving action potential. Summation occurs when the time constant is sufficiently
long and the frequency of rises in potential are high enough that a rise in potential

32. begins before a previous one ends. The amplitude of the previous potential at the point
where the second begins will algebraically summate, generating a potential that is
overall lager than the individual potentials. This allows the potential to reach the
thereshold to generate the action potential.
Thus successive postsynaptic potentials caused by discharges from a single pre-
synaptic, if they occur rapidly enough, can summate in the same way that postsynaptic
potentials may summate from widely distributed terminals over the surface of a neuron.
The degree of temporal summation is directly proportional to time – constant;
and it occurs when the second potential arrises before the 1st has decreased.
Temporal summation is involved in vision. The inverse proportion of intensity
and time, applies as long as the stimulus is no greater than 0.1 second. For example, at
0.1 second, 130 quanta are absorbed, un any matter of provision, but when raised to 1
second there is a lesser rate of summation, needing 230 quanta to compensate for the
decrease in intensity. The frequency of vision is function of frequency of flashes, so the
longer the stimulus, the better chance it can attain the number of quanta needed for
vision.
25 – Conduction velocity of the action potential, its determiants.
When a region of an unmyelinated axonal membrane is depolarized sufficiently
by a depolarizing stimulus (e.g., a synaptic potential in a neuron) to reach a threshold

33. potential, voltage-gated Na+ channels open, Na+ flows into the axoplasm, and an action
potential is generated in that region of the axon. Some of the current generated by the
action potential spreads by electrotonic conduction (passive spread) to an adjacent
region of the axon. The passive spread of current occurs by movement of electrons, and
movement of Na+ ions is not required. At the adjacent region, the passive spread of
current results in opening of voltage-gated Na+ channels, influx of Na+ into the
axoplasm, and generation of an action potential. In other words, the passive spread of
voltage along the length of an axon results in an active regeneration process.
The propagation of an action potential along the axon depends on the cable
properties of the axon. The larger the diameter of the axon, the lower the resistance
there is to the flow of current along its length. Therefore, the conduction velocity
(propagation of action potential) along the length of the axon can be increased by
increasing its diameter. For example, the axons of stellate ganglion neurons in the squid
are about 1 mm in diameter (1000 times larger than the axons of mammalian neurons).
The conduction of action potential in these squid giant axons is faster than in
mammalian axons. The squid needs these fast conducting axons for faster contraction of
the mantle muscles that produce a jet propulsion effect needed for quick escape from
predators.
In vertebrates, the conduction velocity is increased by myelination of axon. A
myelin sheath consists of about 1-mm lengths of as many as 300 concentric layers of
membrane around a single axon. In the peripheral nervous system, myelin is formed by
Schwann cells. In the central nervous system, oligodendrocytes form the myelin. Nodes
of Ranvier (bare segments of the axonal membrane with a very high density of voltage-
gated Na+ channels) are present in between the segments of the myelin sheath. The
myelinated segments of an axon are not excitable and have a high resistance to the
leakage of current across them. On the other hand, passive spread of current can
generate an intense current at the nodes of Ranvier due to the presence of a high density
of voltage-gated Na+ channels.
When a depolarizing stimulus (e.g., a synaptic potential in a neuron) arrives at a node of
Ranvier, Na+ channels open, there is an influx of Na+ ions, and an action potential is
generated at that node. Some current generated by the action potential spreads passively
to the next node of Ranvier, and depolarization of the membrane at this node results in
the generation of an action potential. By this time, Na+ channels at the preceding node
are inactivated, K+ channels open, and repolarization occurs. Thus, the action potential
propagates along a myelinated axon by saltatory conduction (i.e., the jumping of an
action potential from one node to another). Myelination of an axon has two advantages:
(1) conduction is very rapid along an axon, and (2) there is a conservation of metabolic
energy because excitation is restricted to the nodal regions that are relatively small (0.5
µm).
Conduction is also influenced by temperature, a high temperature leads to a
higher conduction velocity
We can also note that the spinocerebellar tract has highest conduction velocity.
26 – Electrical and chemical transmission at synapses.
Types of Synaptic Transmission:

34. Two types of synaptic transmission electrical and chemical are recognized in the
nervous system. It should be noted that the electrical synapses are relatively less
common than the chemical synapses in the mammalian nervous system.
Electrical Transmission
In electrical transmission between the nerve cells, the current generated by an
impulse in one neuron spreads to another neuron through a pathway of low electrical
resistance. Electrical synapses occur at gap junctions. In an electrical synapse, ion
channels connect the cytoplasm of the presynaptic and postsynaptic cells. In the adult
mammalian central nervous system, electrical synapses are present where the activity of
neighboring neurons needs to be highly synchronized. For example, hormone-secreting
neurons in mammalian hypothalamus are connected with electrical synapses so that they
fire almost simultaneously and secrete a burst of hormone into the circulation.
At an electrical synapse, the current generated by voltage-gated channels at the
presynaptic neuron flows directly into the postsynaptic neuron. Therefore, transmission
at such a synapse is very rapid (<0.1 msec). At some synapses (e.g., in the giant motor
synapse of crayfish), the current can pass in one direction (from presynaptic to
postsynaptic neuron) but not in the reverse direction. Such synapses are called rectifying
or unidirectional synapses. At other synapses, the current can pass equally well in both
directions. Such synapses are called nonrectifying or bidirectional synapses. Most
electrical synapses in mammalian nervous system are believed to be the nonrectifying
type.
Chemical Transmission:
At chemical synapses, there is no continuity between the cytoplasm of the
presynaptic terminal and postsynaptic neuron. Instead, the cells are separated by
synaptic clefts, which are fluid-filled gaps (20-50 nm). The presynaptic and
postsynaptic membranes adhere to each other due to the presence of a matrix of
extracellular fibrous protein in the synaptic cleft. The presynaptic terminal contains
synaptic vesicles that are filled with several thousand molecules of a specific chemical
substance, the neurotransmitter.
Pyramid-like structures consisting of proteins arise from the intracellular side of
the presynaptic terminal membrane and project into the cytoplasm of the presynaptic
terminal. These pyramids and the membranes associated with them are called active
zones and are the specialized release sites in the presynaptic terminal. The vesicles
containing the neurotransmitter are aggregated near the active zones.
Mechanisms of Transmitter Release:
An action potential depolarizes the presynaptic nerve terminal, voltage-gated
Ca channels located in the presynaptic terminal membrane open, Ca2+ permeability
2+
increases, and Ca2+ enters the terminal. These events cause the membrane of the
27 – Excitatory and inhibitory neurotrasmitters.
Neurotrasmitter: chemical substance that is synthesized in a neuron, released at a
synapse following depolarization of the nerve terminal (usually dependent on influx of

35. calcium ions), which binds to receptors on the postsynaptic cell and/or presynaptic
terminal to elicit a specific response.
(1) the substance must be synthesized in the neuron, and the enzymes needed for
its synthesis must be present in the neuron;
Small Molecule it must be released in sufficient quantity to elicit a response from the
(2) Gaseous
Neurotransmittersneuron or cell located in the effector Neurotransmitters
postsynaptic Neuropeptides organ;
Acetylcholine(3) mechanisms forOpioid peptides Nitric oxide neurotransmitter from the
removal or inactivation of the
Excitatory amino acids exist; and β-endorphin,
synaptic cleft must
Glutamate (4) it should mimic the action of the endogenously released neurotransmitter
Methionine-
Aspartate administered exogenously at or near a synapse.
when enkephalin
Inhibitory amino acids Leucine-enkephalin
GABA Endomorphins
Glycine Nociceptin
Classes of
Biogenic amines Substance P Neurotrans-
Catecholamines mitters
Dopamine
Norepinephrine
Epinephrine
Indoleamine
In the CNS, a neuron is contantly bombarded by neurotrasmitters, each of which
Serotonin (5-
can generate or modify a synaptic potential.
hydroxytryptamine, [5-HT])
Neurotrasmitters that move the membrane potential towars depolarization with
Imidazole amine
the resultant production of an action potential are known as excitatory neurotrasmitters.
Histamine
Neurotrasmitters that move the membrane away from depolarization by making
Purines
the resting membrane potential more negative, the membrane is hyperrepolariyed, are
ATP
known as inhibitory neurotrasmitters.
Adenosine
Because the postsynaptic response is actually elicited by the receptor rather than
by the trasmitters, the postsynaptic receptor determines whether a given
neurotransmitter will be excitatory or inhibitory. Some neurotrasmitters can have either
effect, depending on the type of postsynaptic receptor present.
Excitatory: Acetylcholine, glutamate, aspratate..
Inhibitory: Dopamine, adenosine, serotonin, histamine, GABA…
Both: Epinepherine, norepinepherine, glycine
Acetylcholine
Neurotransmitter in both the peripheral nervous system (PNS) and central
nervous system (CNS). Acetylcholine is one of many neurotransmitters in the
autonomic nervous system (ANS) and the only neurotransmitter used in the somatic
nervous system. It is also the neurotransmitter in all autonomic ganglia.
In the peripheral nervous system, acetylcholine activates muscles, and is a major
neurotransmitter in the autonomic nervous system. When acetylcholine binds to
acetylcholine receptors on skeletal muscle fibers, it opens ligand gated sodium channels
in the cell membrane. Sodium ions then enter the muscle cell, stimulating muscle
contraction. Acetylcholine, while inducing contraction of skeletal muscles, instead

36. induces decreased contraction in cardiac muscle fibers. This distinction is attributed to
differences in receptor structure between skeletal and cardiac fibers.
In the autonomic nervous system, acetylcholine is released in the following sites:
• all pre- and post-ganglionic parasympathetic neurons
• all preganglionic sympathetic neurons
o preganglionic sympathetic fibers to suprarenal medulla, the modified
sympathetic ganglion; on stimulation by acetylcholine, the suprarenal
medulla releases epinephrine and norepinephrine
• some postganglionic sympathetic fibers
o sudomotor neurons to sweat glands.
In the central nervous system, ACh has a variety of effects as a
neuromodulator, e.g., for plasticity and excitability. Other effects are arousal and
reward. Damage to the cholinergic system in the brain has been suggested to play a role
in the memory deficits associated with Alzheimer's Disease.
Types of acetylcholine receptors:
• Nicotinic AChRs are ionotropic receptors permeable to sodium, potassium, and
chloride ions. They are stimulated by nicotine and acetylcholine. They are of two
main types, muscle type and neuronal type. The former can be selectively blocked
by curare and the latter by hexamethonium. The main location of nicotinic AChRs is
on muscle end plates, autonomic ganglia (both sympathetic and parasympathetic),
and in the CNS.
• Muscarinic receptors are metabotropic, and affect neurons over a longer time
frame. They are stimulated by muscarine and acetylcholine, and blocked by
atropine. Muscarinic receptors are found in both the central nervous system and the
peripheral nervous system, in heart, lungs, upper GI tract and sweat glands.
Glutamate:
Some of the important physiological and clinical considerations relevant to
glutamate are as follows.
• Glutamate has been implicated as a transmitter in a variety of circuits in the
brain. E.g. excitatory amino acids may be involved in learning and memory
processes, as well as motor functions.
Dopamine is a neurotransmitter occurring in a wide variety of animals. In the
brain, it functions as a neurotransmitter, activating the five types of dopamine receptors

37. — D1, D2, D3, D4 and D5, and their variants. Dopamine is produced in several areas of
the brain, including the substantia nigra and the ventral tegmental area. Dopamine is
also a neurohormone released by the hypothalamus. Its main function as a hormone is to
inhibit the release of prolactin from the anterior lobe of the pituitary.
Epinepherine: when in the bloodstream, it rapidly prepares the body for action
in emergency situations. The hormone boosts the supply of oxygen and glucose to the
brain and muscles, while suppressing other non-emergency bodily processes. It
increases heart rate and stroke volume, dilates the pupils, and constricts arterioles in the
skin and gastrointestinal tract while dilating arterioles in skeletal muscles. It elevates the
blood sugar level by increasing catabolism of glycogen to glucose in the liver, and at the
same time begins the breakdown of lipids in fat cells. Like some other stress hormones,
epinephrine has a suppressive effect on the immune system.
Epinephrine's actions are mediated through adrenergic receptors. Epinephrine is a
non-selective agonist of all adrenergic receptors. It activates α1, α2, β1, and β2 receptors
to different extents. Specific functions include:
• It binds to α1 receptors of liver cells, which activate inositol-phospholipid
signaling pathway, signaling the phosphorylation of glycogen synthase and
phosphorylase kinase (inactivating and activating them, respectively), leading to
the latter activating another enzyme—glycogen phosphorylase—which catalises
breakdown of glycogen (glycogenolysis) so as to release glucose to the
bloodstream. Simultaneously protein phosphatase-1 (PP1) is inactivated, as in
the active state PP1 would reverse all the previous phosphorylations.
• Epinephrine also activates β-adrenergic receptors of the liver and muscle cells,
thereby activating the adenylate cyclase signaling pathway, which will in turn
increase glycogenolysis.
β2 receptors are found primarily in skeletal muscle blood vessels where they trigger
vasodilation. However, α-adrenergic receptors are found in most smooth muscles and
splanchnic vessels, and epinephrine triggers vasoconstriction in those vessels.
Epinepherine is found in the spinal cord, hypothalamus, thalamus and
periaqueducts.
Serotonin:
Serotonin-containing cells in the raphe regions of the brainstem are believed to
play a role in descending pain-control systems. Other serotonin-containing neurons may
play a role in mediating affective processes such as aggressive behavior and arousal.
Serotonin synthesized in the pineal gland serves as a precursor for the synthesis of
melatonin, which is a neurohormone involved in regulating sleep patterns. Serotonin is
also believed to play an important role in depression.
Histamin:
Histamine has been implicated as a transmitter in the regulation of food and
water intake, as well as in thermoregulation and autonomic functions.

38. GABA:
• GABA is an inhibitory transmitter in many brain circuits. E.g, GABA is used as
an inhibitory neurotransmitter by the Purkinje cells in the cerebellum. Alteration
of GABAergic circuits has been implicated in neurological and psychiatric
disorders like Huntington's chorea, Parkinson's disease, senile dementi…
• Therefore, dietary deficiency of vitamin B6 can lead to diminished GABA
synthesis. In a disastrous series of infant deaths.. GABA content in the brain of
these infants was reduced. Subsequently, there was a loss of synaptic inhibition
that caused seizures and death.
• Since epileptic seizures can be facilitated by lack of neuronal inhibition, increase
in the inhibitory transmitter, GABA, is helpful in terminating them
• Barbiturates act as agonists or modulators on postsynaptic GABA receptors and
are used to treat epilepsy.
28 – Excitatory and inhibitory postsynaptic potentials.
Postsynaptic potentials are changes in the membrane potential of the
postsynaptic terminal of a chemical synapse. Postsynaptic potentials are graded
potentials, and their function is to initiate or inhibit action potentials. They are caused
by the presynaptic neuron releasing neurotransmitters from the terminal button at the
end of an axon into the synaptic cleft. The neurotransmitters bind to receptors on the
postsynaptic terminal, which may be a neuron or a muscle cell in the case of a
neuromuscular junction. These are collectively referred to as postsynaptic receptors,
since they are on the membrane of the postsynaptic cell. Neurotransmitters bind to their
receptors by having a particular shape or structure, somewhat like the way a key fits
into certain locks.
Postsynaptic potentials are subject to summation, spatially and/or temporally.
Excitatory postsynaptic potential (EPSP) is a temporary depolarization of
postsynaptic membrane potential caused by the flow of positively charged ions into the
postsynaptic cell as a result of opening of ligand-sensitive channels. A postsynaptic
potential is defined as excitatory if it makes it easier for the neuron to fire an action
potential. IPSPs are sometimes caused by an increase in positive charge outflow. The
flow of ions that causes an EPSP is an excitatory postsynaptic current (EPSC).
Inhibitory postsynaptic postsynaptic potentials.
An inhibitory postsynaptic potential (IPSP) is a synaptic potential that
decreases the chance that a future action potential will occur in a postsynaptic neuron or
α-motoneuron.. They can take place at all chemical synapses which utilize the secretion

39. of neurotransmitters to create cell to cell signaling. Inhibitory presynaptic neurons
release neurotransmitters which then bind to the postsynaptic receptors; this induces a
postsynaptic conductance change as ion channels open or close. An electrical current is
generated which changes the postsynaptic membrane potential to create a more negative
postsynaptic potential. Depolarization can also occur due to an IPSP if the reverse
potential is between the resting threshold and the action potential threshold. Another
way to look at inhibitory postsynaptic potentials is that they are also a chlorine
conductance change in the neuronal cell because it decreases the driving force.
In general, a postsynaptic potential is dependent on the type and combination of
receptor channel, reverse potential of the postsynaptic potential, action potential
threshold voltage, ionic permeability of the ion channel, as well as the concentrations of
the ions in and out of the cell; this determines if it is excitatory or inhibitory. IPSPs
always want to keep the membrane potential more negative than the action potential
threshold and can be seen as a “transient hyperpolarization” EPSPs and IPSPs compete
with each other at numerous synapses of a neuron; this determines whether or not the
action potential at the presynaptic terminal will regenerate at the postsynaptic
membrane. Some common neurotransmitters involved in IPSPs are GABA and glycine.
29 – Describe structural arrangement of the neuromuscular junction and its
function.
The neuromuscular junction: The skeletal muscle fibers are innervated by large,
myelinated nerve fibers that originate from large motorneurons in the anterior horns of
the spinal cord. Each nerve fiber, after entering the muscle belly, normally branches and
stimulates from three to several hundred several skeletal muscle fibers. Each nereve
endings makes a junction, neuromuscular junction, with the muscle fiber near its
midpoint. The action potential initiated in the muscle fiber by the nerve signal travels in
both directions towards the muscle fiber ends.
The nerve fibres forms a complex of branching nerve terminals that invaginate
into the surface os the muscle fiber but lie outside the muscle fiber plasma membrane.
The entire structure is called the motor end plate. It is vovered by one or more Scwmann
cells that insulate it from the surronfing fluids.
In the junction between a single axon terminal and the muscle fiber membrane,
the invaginated membrane is called the synaptic gutter or synaptic trough, and the space
between the terminal and the fiber membrane is called the synaptic space or synaptic
cleft. This space is 20 to 30 nanometers wide. At the bottom of the gutter are numerous
smaller folds of the muscle membrane called subneural clefts, which gratly increase the
surface area at which the synaptic transmitter can act.
In the axon terminal are many mitochondria that supply ATP, the energy source
that is used for the synthesis of an excitatory transmitter acetylcholine. The
acetylcholine in turn excites the muscle fiber membrane. Acetylcholine is synthetized in
the cytoplasm of the terminal, about 300.000 of which are normally in the terminals of a
single end plate. In the synaptic space are large quantities of the enzyme
acetylcholinesterase, which destroys acetylcholine a few milliseconds after it has been
released from the synaptic vesicles.
When a nerve impulse reaches the neuromuscular junction, about 125 vesicles of
acetylcholine are released from the terminals into synaptic space.

40. On the inside surface of the neural membrane are linear dense bars. To each side
of each dense bar are protein particles that penetrate the neural membrane; these are
voltage-gated calcium channels. When an action potential spreads over the terminal,
these channels open and allow calcium ions to diffuse from the synaptic space to the
interior of the nerve terminal. The calcium ions, in turn, are believed to exert an
attractive influence on the acetylcholine vesicles, drawing them to the neural membrane
adjacent to dense bars. The vesicles then fuse with the neural membrane and empty their
acetylcholine into the synaptic space by the process of exocytosis.
Myastenia gravis and Lambert-Eaton syndrome.
Myastenis gravis is a serious and sometimes fatal disease in which skeletal
muscles are weak. It is caused by the formation of circulatory antibodies to the muscle
type of nicotinic acetylcholine receptors. These antibodies destroy some of the receptors
and bind others to neighbouring receptors triggering their removal by endocytosis.
Drugs affecting transmission at neuromuscular junction:
a) some drugs act on acetylcholine thus stimulating the muscle fiber, e.g.
nicotine
b) some drugs may block transmission e.g. muscle relaxant.
c) some drugs stimulate neuromuscular junction by inactivation ach-
acetylcholinesterase e.g. physostigmine
30 – Presynaptic inhibition and posttetanic potentiation
In addition to the inhibition caused by inhibitory synapses operating at the
neuronal membranes which is called post-synaptic inhibition, another type of inhibition
often ocuurs in the presynaptic terminals before the signals even reaches the synapse –
pre-synaptic inhibition.
Pre-synaptic inhibition is the phenomenon that occurs when a presynaptic
neuron exerts inhibitory influences through transmitters at an axo-axonic synapse with
the terminal in a postsynaptic neuron.
In presynaptic inhibition, the inhibition is caused by discharge of inhibitory
synapses that lie on the presynaptic terminals nerve fibrils before their endings
terminate on the post-synaptic neuron. In most instances, the inhibitory transmitter
released is GABA, this has the specific effect of opening ion channels, allowing CL- to
diffuse into the terminal fibril.
Therefore the action potential itself becomes greatly reduced, thus also reducing
the degree of excitation of the postsynaptic neuron.
Presynaptic inhibition occurs in many of the sensory pathways in the nervous
system.
3 mechanisms of presynaptic inhibition are seen:
⇒ Activation of the presynaptic receptors increases Cl- conductance, and this has been
shown to decrease the size of the action potentials rwaching the excitatory ending.
⇒ This in turn reduces Ca++ entry and consequently the amount of excitatory
transmitter released. Voltage-gated K+ channels are also opened and the resulting
K+ also decreases Ca++ influx.
⇒ Evidence for direct inhibition of transmitter release independent of Ca++ influx into
the excitatory ending is evident.

41. Post-tetanic potentiation
If we stimulate motor unit and correlate it with the srenght of muscle contraction we
can observe the principles of frequency summation and tetanization. First, with a
lower rate of stimulation (times per second) and then increasing the frequency there
comes a point where each new contraction occurs before the preeciding one is over.
As a result, the second contraction is added partially to the first, so that the total
strength of contraction rises progressively with increasing frequency. When the
frequency reaches a critical level, the successive contractions eventually become so
rapid that they fuse together, and the whole muscle contraction appears to be
completely smooth and continuos. This is called tetanization. At a slightly higher
frequency, the strength of contraction reaches its maximum, so that any additional
increase in frequency beyond that point has no further effect in increasing
contractile force. This occurs because enough calcium ions are maintained in the
muscle sarcoplasm, even between action potentials, so that full contractile state is
sustained without allowing any relaxation between the action potentials.
The tetanizing stimulation causes Ca++ to accumulate in the presynaptic neuron
to such a degree that the intracellular binding sites that keep cytoplasm Ca++ low are
overwhelmed.
Postetanic potentiation is opposite to habituation
31 – Spontaneously active neurons:
Many neurons do not maintain a steady resting potential but fire impulses
spontaneously.
Two patterns often seen are:
a) regular firing or “beating”
b) grouped firing or “bursting”
In spontaneously active neurons, resting Na+ conductance is high, the leakage
current depolarizes and the threshold is crossed, and an action potential is fired.
a) In regular firing neurons: in these neurons the membrane potential is less
negative due to their possession of high Na+ leak conductance and low K+ leak
conductancy. As the membrane potential moves to a more positive value, the thereshold
is crossed quickly. After an impulse, voltage K+ channels open and the membrane is
hyperepolarized. There is then a return to the resting potential due to to Na+ leakage.
b)In bursting neurons: these neurons have the same membrane channels as
firing neurons, they regulate action potentials during a burst. In depolarization of
an action potential, voltage-gated Ca++ channels are opened to allow Ca++.
They are slow, voltage-gated channels allow Na+, Ca++ exchange. This slow
depolarization predominate during the impulse generating phase of the burst
cycle. K+ channels which are activated by Ca++ are responsible for
hyperrepolarisation (calcium-gated K+ channel).
In bursting neurons, the leakage is slow, voltage dependent depolarizing
channels (Na+, Ca++) generate the burst in a action potential. During this phase,
Ca++ enters the cell by the voltage dependent Ca++ channels and activates Ca++

42. gated K+ channels. K + hyperrepolarizes the membrane until the moment when
Ca++ is pumped out of the cell or sequestrated.
Spontaneous active neurons are important for circuits controlling respiration,
locomoytion as well as other activities
32 – Coding of sensory information
Cells specialized to respond to a specific environmental stimuli are termed
sensory receptor cells.
a) a neuron specialized for sensory reception
b) a receptor cell connected to an afferent neuron
c) sense organ composed of receptor cells and additional accessory to transform
the stimulus.
Receptor cells respond specifically to certain stimuli (receptor specificity) , there
are 4 major groups of receptors in mammals:
a) thermoreceptors
b) chemoreceptors
c) photoreceptors
d) mechanoreceptors
A stimulus is characterized by its modality, intensity, duration and location.
Sensation evoked by a stimulus depends on the part of the brain that has been
stimulated – Pacinian corpuscle stimulation either by touch or imitation from a
tumour produces a touch sensation.
Sensory information are processed by the thalamus and is transmitted to the
cerebral cortex where the nerve pathways from a particular sense organ are stimulated,
the sensation evoked is that for which the receptor is specialized, no matter how long
the pathway or where along the pathway the activity has been initiated.
Law of projection: no matter where a particular sensory pathway is stimulated
along its course to the cortex, the conscious adaptation produced is referred to the
location of the receptor, (e.g. phantom limb sensation seen in amputated people or in
neurosurgical experiments with conscious patients, stimulation of specific part of cortex
may produce tickling sensations)