1.
-Dr. Ashish Arya
Moderator: Dr. M. S. Reddy
GABA

2.
 Introduction
 Discovery
 Synthesis, storage and degradation
 Receptors
 Neuropsychiatric implications
 Drugs

3.
Introduction
 Gamma Amino Butyric Acid (GABA) is the
major inhibitory neurotransmitter of the
mammalian CNS.
 It is broadly distributed in the brain.
 Implicated in broad range of neuropsychiatric
disorders like seizures, anxiety disorders,
schizophrenia, alcohol dependence etc.

4.
Discovery
 In 19th century – was know as a metabolite of
plant and microorganisms
 In early 20th century - was isolated as an amino
acid in the brain of mouse through paper
chromatography.
 In 1950 Robert and Frankel discovered GABA in
human brain.
 GABA patches: inhibitory effects

5.
Synthesis and Storage
 Synthesised from amino acid L- Glutamic acid
 Glutamic acid Decarboxylase (GAD) present in
neurons and peripherally in pancreatic islet cells
and body fluids.
 It catalysis the removal of α- carboxyl group.
 GAD 65 and GAD 67 genes encoding GAD

6.
Termination of action
 GABA transporter (GAT)
 GAT 1 is identified as a presynaptic receptor.
While GAT 2-4 receptor location have yet to be
identified.
 Tiagabine blocks GAT1 receptor – increase in
synaptic GABA concentration – anticonvulsant
action.

7.
Termination of action

8.
 GABA is catabolised by GABA transaminase
(GABA-T).
 GABA-T is a cell surface, membrane bound enzyme
expressed by neurons and glia, oriented towards
extracellular compartment.
 Inhibited by valproic acid and vigabatrin.

9.
Receptors
 Three major types
I. GABA A
II. GABA B
III. GABA C

10.
 GABA A
 Ligand gated ion channel.
 Distributed throughout the brain.
 It is a heteropentamer, made of five subunits with
each subunit containing four α helical membrane
spanning.
 Ligand binds at the interface between α and β
domain.

11.
 There are many different types of GABA A
receptors depending on the type of subunit
present.
 Subunits also called isoforms – alpha(1-6),
beta(1-3), gamma(1-3), delta, epsilon, pi, theta
and rho.
 Different types of GABA A receptors are present
in different regions of the brain and at different
levels of development.

12.
 GABA A receptor when activated, mediates an
increase in the conductance.
 Increase in the influx of Cl- ions causing
membrane hyperpolarization.
 Increase in the threshold for generating action
potential.
 Inhibitory action

13.
 Allosteric modulation
 The site where modulators bind is different from
the site of binding of GABA agonist – known as
“allosteric” site and the modulator is called
“allosteric modulator”. The modulator has no
activity of its own.
 Positive Allosteric Modulation: ligand binds
allosteric site and enhance the action of
neurotransmitter. E.g.BZD
 Negative Allosteric Modulation: ligand binds to
the allosteric site while an agonist is also bound
and the channel opens less frequently then when

14.
 GABA A receptors with alpha 4/6 and delta
subunit are insensitive to benzodiazepines.
 Binds to modulators – naturally occurring
neurosteroids, alcohol and some general
anesthetics.
 Located extrasynaptically. Regulated by
extracelullar GABA molecule that has escaped
reuptake and enzymatic destruction
 Mediate tonic inhibition of postsynaptic neuron
 Not sensitive to BZD – no anxiolytic actions of
BZD

15.
 GABA A receptor with alpha 1/2/3, beta, gamma 2/3.
 Postsynaptic in location – phasic inhibition. Bursts of
inhibition triggered by peak concentration of
synaptically released GABA.
 Sensitive to BZD – Anxiolytic actions.
 Alpha 1 – most important for regulating sleep –
target for various sedative hypnotic agents.
 Alpha 2/3 most important for regulating anxiety.
 Abnormal expression of alpha 2, gamma 2 or delta

16.
 GABA B
 Differentiated from GABA A by
 Insensitive to GABA A antagonist Bicuculline.
 Activated by Baclofen
 Member of G-protein couples receptor. Dimer of
two seven transmembrane spanning subunits.
 Widely distributed throughout the CNS.

17.
 Located both pre- and post-synaptically.
 Presynaptically- auto- and hetero-receptor. Inhibits
neurotransmitter release.
 Postsynaptically – inhibitory – long lasting
hyperpolarization by activating K+ channel.
 GABA B 1 genes –
 GABA B (1A) – granule cell layer
 GABA B (1B) – Purkinje cells.
 GABA B 2 genes

18.
 All GABA B agonist and antagonist bind to the
extracellular domain of GABA B (1) subunit.
 GABA B receptor antagonist blocks the action of
Gamma Hydroxybutyrate (GHB).
 GABA C
 Ligand gated ion channel.
 Part of the inhibitory Cl- channel.
 Physiological role is not yet discovered.

19.
Anatomy of the GABA system

20.
 Corticolimbic region:
 Localised in the intrinsic/local circuit neurons
 Comprise minority of cortical neurons but exhibit
profound degree of inhibition on the activity of
glutamatergic pyramidal cells.
 In the cortex, GABAergic interneurons are the
primary site of colocalizaton of neuropeptides.

21.
 Striatum:
 GABAergic directly project to the substantia nigra
pars reticulata
 Striatal GABergic neurons also project to the globus
pallidus to synapse on the pallidal-subthalamic
GABAergic neurons that regulate the excitatory
output from the subthalamic nucleus.
 Cerebellum:
 In cerebellum, GABAergic Purkinje cells are its main
efferent system

22.
Neuropsychiatric implications
I. Anxiety disorders
 Including phobic anxiety disorder, GAD, PTSD,
Panic disorder – where core feature is some
form anxiety or fear coupled with some form of
worry.
 Amygdala central circuit – amygdala plays
central role in the expression of fear and anxiety.
 Cortico-Striatal-Thalamo-Cortical (CSTC) loop –
linked to worry and obsessions across the
spectrum of anxiety disorders.

23.
 Anxiety can also be triggered by memories stored
in the Hippocampus, which activates the
Amygdala, in turn causing other brain regions to
activated and generate fear.
 Particular feature of PTSD

24.
 GABA is the principal inhibitory neurotransmitter
in the brain and serves an important regulatory
role in in reducing the activity of many neurons
including those in Amygdala and CSTC loop.
 GABAergic dysfunction has been associated with
anxiety disorders, esp with panic disorder.
 Magnetic Resonant Spectroscopy reveals
significant reduction in GABA levels in the ACC
and Basal ganglia.

25.
 PET scanning reveals highly selective reduction
in BZD receptor sites bilaterally in the insular
cortex in Panic disorder.
 Genomwide screen has shown significant
linkage at 15q in a region containing GABA a
receptor subunit genes and panic disorder.

26.
II. Mood disorders
 Magnetic Resonant Spectroscopy reveals
significant reduction in both GABA and
Glutamate in Prefrontal cortex in Major
Depressive Disorder.
 Post mortem studies revealed up regulation of
the GABA receptors alpha1 and 2 subunits,
consistent with a reduction in GABAergic
neurotransmission.
 Reduced levels of GABA in occipital cortex in
episodes of major depressive disorder

27.
 In animal studies – valproate, carbamazapine,
lithium and lamotrigine a/w in increase in GABA
turnover in brain.
 Endocrinal hypothesis: estrogen induces
downregulation of GAD resulting in inhibitory
action on GABA formation resulting in increased
activity of pyramidal cells.

28.
III. Schizophrenia
 Corticobrainstem glutamate pathways and
NMDA receptor function hypothesis
 Descending glutaminergic pathway projects from
cortical pyramidal cells to brainstem
neurotransmitter centres inclusing raphe for
serotonin, VTA and substantia nigra for
dopamine and locus ceruleus for norepinephrine.

29.
 The descending corticobrainstem glutamate
pathway acts as a brake to the mesolimbic
dopamine pathway through an inhibitory GABA
interneuron in the VTA. Which are activated by
NMDA receptors.

30.
 Corticostriatal glutamate pathway (CSTC loop)
 Descending glutaminergic output from the
pyramidal cells in cortex nucleus
accumbens in ventral striatum forming first
leg of the CSTC loop.
 Ascending pathway from thalamus to cortex –
return leg of the CSTC loop.
 GABA neurons located in the thalamus acts as
the sensory filters and prevents too much
sensory input from penetrating the thalamus into
the cortex.

31.
 Dopamine inhibits GABA in CSTC loop
reduces the effectiveness of thalamic filter
opposes the excitatory input of the glutamate
from corticostriatal glutamate projections.

32.
 Mesolimbic dopamine hyperactivity reduces
thalamic inhibition increases cortical
activation
 NMDA receptor hypofunction in corticostriatal
and corticoaccumbens projections
sensory overload.

33.
 Postmortem studies indicated a reduction in the
activity of GAD in the cortex in patients with
schizophrenia.
 Neurochemistry: reduced expression of GAD 67,
Parvalbumin-positive GABAergic interneurons
and the GABA transporter (GAT).
 Upregulation of GABA receptors – supports
hypofunction of presynaptic GABAergic neurons.

34.
 Epilepsy
 In epilepsy, abnormal electrical discharges are
due to hyperexcitable neurons with sustained
postsynaptic depolarization.
 Decreased GABA inhibition of cortical excitability
is one of the proposed mechanism.
 Penicllin induced cortical injury causes seizures
through decreased GABA inhibition.
 BZD and barbiturates reduces seizures by
enhancing GABA receptor current and valproate
through blockade of GABA catabolism.

35.
 Reward circuits
 Mesolimbic dopamine pathway is the final
common pathway of reinforcement and reward in
the brain.
 Reactive reward system: bottom up – provides
motivational and behavioural drive in ascending
mesolimbic pathway.
 Reflective reward system: top down –
connections from prefrontal cortex down to
nucleus accumbens and involved in regulating
impulses and keeping some flexibility of choice.

36.
 Turning reward into goal directed behaviour
 The output of the reward system is the
completion of CSTC loop.
 The striatal/accumbens component of reward
circuitry has output GABAergic neurons that
travel to another part of striatal complex the
ventral pallidum.
 From there the connections go to thalamus and
back to prefrontal cortex where behaviours are
implemented such as learning and activities in
long term rewards and drug seeking behaviour

37.
 Alcohol and reward
 Alcohol reinforcing effects are mediated by its
effects specially on mesolimbic reward circuitry.
 Acts at presynaptic glutamate receptors and
voltage sensitive Calcium channels to inhibit
glutamate release.
 Enhance the GABA release by blocking the
presynaptic GABA B receptors and acts on
postsynaptic GABA A receptors of delta subtypes

38.
 Opiate neurons arise from arcuate nucleus and
projects to the glutamate and GABA neurons.
 Alcohol acts on mu opiate receptors which
increases the dopamine release in the nucleus
accumbens.
 Persistent abuse and dependency on ethanol
result in downregulation of GABA and an
upregulation of NMDA receptors such that
sudden discontinuation results in hyperexcitable
state characterised by delirium tremens.

39.
 Nicotine and reward:

40.
 Varenicline: nicotine partial agonist

41.
 Sleep and Wakefulness
 CSTC loop regulate the arousal and part by
controlling the size of thalamic filter.
 Sleep wake switch: set of circuit present in
hypothalamus that regulate sleep/wake
discontinuously like an “on/off” switch.
 Tuberomammillary nucleus – wake promoter
 Vantrolateral preoptic nucleus(VLPO) – sleep
promoter.

42.
 Orexin containing neurons of lateral
hypothalamus- promotes wakefullness.
 Melatonin sensitive neurons of the
Suprachiasmatic nucleus (SCN) – regulates
circadian input to the sleep/wake switch.

43.
 Insomnia occurs when it fails to filter out sensory input
to the cortex in night and daytime sleepiness when it
filters out too much sensory input to the cortex in the
daytime.