NPP Unit 4 Class 2: Depression

what brain structure/NT is depression linked to?

depression is NOT linked to a single region, it is caused by complex interactions between different circuits and structures which have heterogenous communication (multiple NT systems), especially symptom to symptom

• behavior can be caused by hyper/hypoactivity or hyper/hypocoectivity

…yet we still rely on SSRIs as treatment

50s evidence for monamine theory

• TB patients had increased appetite and vitality when administered with MAO inhibitor (more monoamines)

• opposite effects (patients lost enjoyment) were seen when patients administered with VMAT blocker (fewer monamines)

how was serotonin linked to depression

the antipsychotic imipramine which improved mood

→ imipramine is a SERT (and somewhat NET) transport blocker

→ additionally, suicide victims showed lower 5HT levels in the brain

fluexitine

marketed as prozac, the first SSRI marketed for depression

problems with serotonin theory

• no clear link between low serotonin levels and depression

• disrupting 5HT does not induce depression

• SSRIs increase 5HT levels within hours but does not improve symptoms for weeks

• SSRIs sometimes do not have very robust affects

• post synaptic receptors can be excitatory OR inhibitory (autoreceptors exist)

PFC in a normal functioning brain is important in the…

… integration of sensory information to provide emotional salience

→ aka they provide the information with rewarding or aversive qualities and creates visceral internal reactions

evidence for glutamate role in depression

→ studies found reduced glutamate in the vmPFC in depressive individuals

→ genes involving glutamatergic transmission are associated with depression

→ depressed people have disrupted glutamine in cerebrospinal fluid

glutamate life cycle

1. glutamine is converted to glutamate

2. stored in vesicles via vGLUT

3. released via SNARE mediated exocytosis

4. glu cleared via astrocytes or rel

5. metabolized into glutamine

   ***mGluR2 + mGluR3 = autoreceptors

glutamate → BDNF cascade

1. glutamate binds to AMPA and depolarizes the cell

2. Mg2+ is knocked off of the NMDA receptor

3. Ca2+ can flow in

4. Ca2+ leads to a downstream cascade that produces BDNF

5. BDNF binds to TRKB receptors, which leads to more synaptogenesis and maintenance

AMPA receptors (normal conditions)

• AMPA receptors maintain glutamate signaling under normal conditions (since Mg2+ usually blocks NMDA)

• up regulation of AMPA receptors result of synaptic plasticity (LTP), so more AMPA = better communication

AMPA and depression

• AMPA knockout mice display learned helplessness, decreased 5HT transmission, and disturbed glutamate homeostasis

• fewer AMPA on 5HT = less excitable, and AMPA potentiators lead to effects similar to SSRIs

NMDA (normal conditions)

• promote cell survival processes or activates cell death processes (too much = death, too little = weak synapses)

• moderate activation promotes Ca2+ mediated pathway and second messenger cascade (good for BDNF production + neuroplasticity)

NMDA and depression

studies show altered receptor function and structure

BDNF timeline

• produced during development when neurons activate and Ca2+ is let in - this is essential for synaptic plasticity

  • there’s a lot of BDNF in infancy and childhood, then it is a make as need basis after adolescence

role of BDNF

BDNF increases synaptic plasticity

• increases phosphorylation and membrand insertion of AMPA

• increases number of synapses, dendritic spine maturation, and promotes signaling

  • BDNF binds to TRKB receptors, induces NMDA phosphorylation, which increases opening probability)

BDNF and depression

insufficient BDNF production + signalling = depression/decreased synaptic strength

→ glutamate signaling is critical for maintaining healthy synapses in the areas of the brain associated with mood

early life stress and depression

early life stress:

• decreases BDNF signaling by creating proteins that block BDNF production

• decreases AMPA up regulation

• reduced synaptic maintenance/function (fewer dendrites/dendritic spines)

TRKB

where BDNF binds to create downstream effects of neural plasticity

ketamine mechanism

NMDA antagonist (initially used as an anesthetic)

→ acts on synaptic, extrasynaptic, and heteroceptors from axoaxonic connections

→ creates a very quick antidepressive effect that can be combined with other methods

how is BDNF regulated and what happens to people with MDD

BDNF is highly regulated (too much BDNF = forgetting things)

1. Ca2+ flowing through NDMA receptor = increase of tonic eEF2K activity

2. increased eEF2K = phosphorylation (activation) of eEF2

3. eEF2 phosphorylation silences production and release of BDNF

→ individuals with depression have over activation of eEF2K, so it is good to shut off this mechanism

ketamine and depression: BDNF

1. ketamine blocks synaptic receptors from influxing in Ca2+

2. therefore, eEF2 cannot phosphorylate

3. prevents reduction of BDNF signaling release

ketamine and depression: glutamate

• regulatory GABA heteroceptors with NMDA often synapse onto glu synapses, when too much glu is released it is regulated by GABA release bc the glu activates the GABA

• ketamine blocks these NMDA too leading to glutamate burst

glu burst → neuronal activation → BDNF → synaptogenesis

→ often combined with other ways to promote glutamate bursts (GABAr inverse agonists, mGluR 2/3 antagonist)

LSD mechanism (general)

5HT2A receptor agonist to promote glutamate bursts directly (there are 5HT2A receptors on glutamate neurons that depolarize when activated), these interact with AMPA and NMDA to create strong glutamate bursts promote BDNF (aka synaptic growth + neuralplasticity)!

→ can also act at 5HT2A heteroceptors

LSD mechanism (AMPA + NMDA interaction)

1. LSD had more affinity than serotonin on 5HT2A, so it is more likely to bind and activate/depolarize glu post synaptic neuron

2. his leads to downstream effects that activate AMPA and NMDA receptors

LSD and TRKB

LSD is a positive allosteric modulator for TRKB receptors, enhancing the effect and subsequent plasticity when BDNF binds

therapeutic effects of SSRIs

• SSRIs likely act on the same synapses as LSD, but have a lower affinity and will never be as effective (endogenous 5HT has low affinity so there is more control of post synaptic activation since you don’t need to be as careful)