presantation on depressionpresantation on depression

1. SYNAPTIC MECHANISM
REGULATING MOOD STATE
TRANSITIONS IN
DEPRESSION
•Auther: Puja K. Parekh, Shane
∗
B. Johnson, and Conor Liston
∗
•Journal: Annual Review of
Neuroscience
•Presenter:
Yashu Sharma (24mslsmm05)
Sanjna ( 24mslsmm34)

2. Introduction - The Puzzle of Depression
• Depression is a widespread, episodic illness affecting ~17%
of people in their lifetime.
• It's characterized by transitions between periods of wellness
and depressive episodes.
Core Q. What are the neurobiological mechanisms that drive
these mood state transitions?
• This presentation will explore the role of synaptic plasticity
in both the problem and the solution.

3. The Brain Under Stress: Synapse
Dysfunction
• Converging evidence indicates that synaptic remodeling in stress-
sensitive circuits plays an important role in the emergence of
depressive episodes
• Chronic stress is a major risk factor for depression.
• In animal models, stress leads to physical changes in brain circuits.
Key Effect: Reduction in dendritic spines (synapses) in crucial brain
areas like the prefrontal cortex and hippocampus (Pyramidal
Neurons)
• This leads to impaired communication between neurons.

4. Q. What is Spines ?
• Dendritic spines are microscopic membrane protrusions in
specific subtypes of neurons
• It usually (but not always) contain synapses
The effects of stress and antidepressants on spine density
shown in the Golgi impregnation and in vivo imaging studies
Spines are also classified by their morphology

5. Flopodia
like
Spines
Thin
Spines
Stubby
Mushroo
m
Spines
SPINES
exploratory protrusions on
neurons
highly motile and plastic
neuronal protrusions
small, non-protruding
dendritic protrusions
mature, stable dendritic
protrusions with large heads

6. Synaptic Dysfunction In Depression
Pathophysiology
• Chronic stress is a major risk factor for depression.
• While the brain is adaptive, prolonged stress causes long-
term physical changes to brain cells and their connections (a
process called "allostatic load").
• These changes, driven by stress hormones like
glucocorticoids, involve the remodeling of synapses.
• The effects vary across the brain: most regions lose synapses,
leading to impaired function, while some fear- and anxiety-
related regions gain synapses, becoming overactive
• This physical "rewiring" of the brain due to chronic stress is
believed to underlie the symptoms of depression and anxiety.

7. • Antidepressants works on these wiring system to treat the
depression like disorders
Key brain areas that involve in the stress
and function of antidepressants
AMYGDAL
A
HIPPO.
CORTEX
PFC

9. Hippocampus
• The hippocampus, a crucial brain area for memory, is one of the first
regions shown to be physically damaged by chronic stress and depression
• Stress hormones (glucocorticoids) cause brain cells in this area to shrink
(atrophy) and their connections to weaken, which impairs learning and
memory formation (LTP- long term potentiation)
• chronic stress halts the neurogenesis in the dentate gyrus (DG),part of
hippocampus
• A key reason for this damage is that stress reduces the levels of a protein
called BDNF (Brain-Derived Neurotrophic Factor), which acts like a
fertilizer for brain cells, helping them grow and connect.

10. The resulting damage to the hippocampus contributes
DEFICITS IN
ABILITY TO
COPE WITH
STRESS
DEFICITS IN
SOCIAL
INTERACTION
S
DEFICITS IN
REWARD
LEARNING
MEMORY
PROBLEM

11. mPFC – ''A control center''
• The medial prefrontal cortex (mPFC) is the brain's hub for
cognitive control and for regulating the body's stress response.
• Chronic stress causes significant damage to this area,
impairing its function and structure.
• stress weakens the connections between neurons (impairing
LTP) and reduces their ability to communicate.
• This damage leads to problems with mPFC-dependent
behaviors like decision-making and mental flexibility.
• Structurally, the neurons physically shrink, losing their
branches (dendrites) and connection points (spines).

12. • This damage leads to problems with mPFC-
dependent behaviors like decision-making and
mental flexibility.
• mPFC is also responsible for "top-down" control over
fear centers like the amygdala

13. Amygdala – ''Emotional center''
KEY
REGIONS
BLA
BNS
T
CeA
Baso
lateral
amygdala
Central
amygdala
Bed
nucleus of
strea
terminalis

14. • The amygdala, the brain's emotional center, reacts to chronic stress
in the opposite way to the hippocampus and prefrontal cortex
• Instead of shrinking, the basolateral amygdala (BLA) becomes
hyperactive and physically grows larger and more complex (a
process called hypertrophy).
• Stress increases the brain's "fertilizer" (BDNF), the number of
connection points (spines), and the complexity of neuron branches
in this area.
• There is increase in dendrite complexity and spine density
• In BNST also there is increase in dendrite complexity
• In CeA, it shows a mixed results , spine density goes down means it
loses some connections, while it's overall complexity is variable
• These effects can contribute to the chronic and recurring nature of
disorders like depression and PTSD.

16. NAc – key region in reward system
• The nucleus accumbens (NAc) and ventral tegmental area (VTA),
which form the brain's core reward and motivation circuit, generally
become hyperactive after chronic stress, with their neurons growing
more connections (spines).
• This is a key finding in animal models and aligns with brain imaging
studies showing altered reward circuits in depressed patients.
• A crucial factor in this process is the VTA, which becomes overly excitable.
• Increased signaling of the brain's "fertilizer" molecule, BDNF, in this
specific area seems to make an individual more susceptible to the
negative effects of stress.
• Experiments show that artificially calming down this VTA hyperactivity
can reverse the effects of stress, confirming that this over-activity is a key
part of the problem.

18. lateral habenula (LHb) - ''anti-reward
center''
• The lateral habenula (LHb), the brain's "anti-reward center,"
becomes hyperactive following chronic stress, suggesting it's a key
driver of depression.
• Its job is to process negative experiences and disappointment. In
response to stress, the "go" signals flowing into the LHb become
too strong, causing its neurons to fire excessively.
• This over-activity then causes a domino effect, sending powerful
"stop" signals to the brain's key reward (dopamine) and mood
(serotonin) centers, leading to symptoms of depression.
• Crucially, treatments that calm down the LHb's hyperactivity, such
as deep brain stimulation and the fast-acting antidepressant
ketamine, have been shown to relieve depression, confirming that
this over-activity is a central part of the problem.

20. Evidence for Synapse Dysfunction in Human
Studies
• Evidence for synapse dysfunction in human depression
comes from two main sources:
Postmortem brain
analysis
 It show that neurons in key areas
like the PFC are smaller and the
cortex itself is thinner.
 More detailed analysis confirms
a physical reduction in the
number of synapses and
genes/proteins that needed to
maintain them in regions
like PFC, HIPPO. & NAc
Neuroimaging
 Neuroimaging studies of
living patients support these
findings.
 Brain scans show a smaller
hippo., altered levels of brain
chemicals (glutamate and
GABA), and reduced functional
connectivity in the brain's
cognitive and mood-regulating
networks.

21. Synaptic plasticity as a Therapeutics Target:
Antidepressants and Synaptic Plasticity:Antidepressants act by
enhancing synaptic plasticity.
1. Initially reconfiguring stress-induced brain states and
2. later sustaining these changes through synaptogenesis.
• Mainly 3 types of antidepressants are used:
1. Monoaminergic Antidepressants.
2. Ketamine.
3. Psychedelics and analogs.

22. 1. Monoaminergic antidepressants:
These drugs (e.g., SSRIs: selective serotonin reuptake
inhibitors) enhance synaptic transmission and plasticity
over weeks, but their effects on synaptogenesis are slow
and modest.
They generally work by: 1. increasing long term
potentiation .
2. increasing dendritic spine
density.
3. facilitates learning-related
plasticity.
• For example: chronic treatment with fluoxetine (an SSRI)
enhances LTP and synaptic transmission.

23. Mechanisms:
Limitations: 1. effect on plasticity: slow and modest.
2. high relapse risk.

24. 2. Ketamine:
A rapid-acting NMDAR ( N-methyl D- aspartate Receptors)
antagonist.
ketamine induces rapid synaptogenesis and circuit
reorganization in the mPFC and hippocampus.
• Low dose of ketamine act as rapid acting antidepressant.
Effects seen ~ 40 minutes.
peak at 24hr., lasting up to: 1-2 weeks.
Evidences:
1.In rodents: Increased spine density in prefrontal neurons
within 24 hours.
2.In humans: show rapid release in glutamate release and
reversal of depression related connectivity changes.

25. 3. Psychedelics and analogs:
• Compounds like psilocybin associated with increasing
dendritic spine density in prefrontal layer 5 pyramidal
neurons by increasing spine formation rates and
enhancing glutamatergic neurotransmission and
persisting for at least 1 month after treatment.
• Non-hallucinogenic analogs (e.g., tabernanthalog)
show similar therapeutic potential.
There’s debate whether hallucination are necessary
for therapeutic effect or not?

26. Overall, all three antidepressants have similar effects on
synaptic plasticity , those effects differ in degree and
the time required to achieve them.
• SSRIs: modest effect, emerge slowly over week.
• Ketamine and psychedelics: rapid, potent effects
after single treatment, but they may not persist
absent additional interventions.

27. The initiating and sustaining mechanisms of rapid acting antidepressants
a. In mPFC, ketamine acts to elevate glutamatergic tone of excitatory pyramidal neurons, via. Disinhibitory
mechanism involves firing interneurons. Ketamine leads to enhanced somatic and spine Ca2+ transients in layer
2/3 pyramidal cells within 1 h and increases multicellular ensemble activity within 3 h of administration.
Ketamine, its metabolite HNK (hydroxynorketamine), and SPs (serotonergic psychedelic) each increase
neurotrophic signaling and AMPAR insertion in mPFC excitatory neurons. The sustained antidepressant effects of
ketamine and psychedelics involve targeted dendritic spinogenesis on excitatory projection neuron.
b. In hippocampal SC to CA1 synapses, ketamine rapidly enhances BDNF release and increases postsynaptic
glutamatergic transmission while a sustained effect involves the delayed increase in pMeCP2 through a BDNF-
dependent mechanism.

28. Defining mechanistic roles for antidepressant-
induced synapse formation:
• Key Question: Is new synapse formation
(synaptogenesis) required for antidepressant effects,
or is it just a side-effect?
Findings from Ketamine Studies:
1.Behavior vs. Spine Growth: Ketamine improves
depressive-like behaviors before new spines form,
means initial effects are due to functional changes in
circuits, not new connections.
2.Sustaining Effects:
New spines appear 12–24 hours after ketamine.
Therefore, Synaptogenesis is not required to start
recovery but is essential to maintain it.

30. Thank you!!