Case 1 - BDNF hypothesis of MDD

Question 1

BDNF synthesis + function

Answer 1

• BDNF is first synthesized as the precursor pre-proBDNF in the endoplasmic reticulum. The pre- domain is cleaved off and proBDNF is transported to the Golgi apparatus. ProBDNF may be secreted in the precursor form or proteolytically cleaved intracellularly or extracellularly to form mature BDNF
• Both pro- and mature forms of the BDNF protein are neuroactive, though the activity of proBDNF and mBDNF have largely opposite effects.
  o ProBDNF binds and activates the pan-neurotrophin receptor p75NTR, a member of the tumor necrosis factor receptor family, promoting apoptosis.
  o mBDNF binds with high affinity to the tyrosine kinase receptor tropomycin receptor kinase B (TrkB).

Question 2

BDNF signalling

Answer 2

• When mature BDNF, or neurotrophins with lesser affinity for TrkB including neurotrophin-4 and neurotrophin-3, bind to the extracellular domain of TrkB, the intracellular domains of the receptor dimerize and autophosphorylate one of three tyrosine residues. Phosphorylation at each residue initiates a distinct signaling cascade: Ras-PI3K-Akt, Ras-MAP kinase-Erk, or phospholipase Cγ[8]. These signaling cascades activate transcription factors such as CREB, resulting in cell proliferation, cell survival, synaptogenesis, and memory formation
  o In the brain, BDNF and TrkB expressed by neurons, astrocytes[15], and microglia[16].
   BDNF is highly expressed in the hippocampus and is found in lower concentrations in the cerebral cortex and brainstem[17].
   TrkB is more widely present –> PFC anf hipp

Question 3

pro-BDF signalling

Answer 3

• ProBDNF binds to pan-neurotrophin receptor P75
  P75 signaling activates transcription factor NFκB via JAK, leading to inflammation and apoptosis
  P75 –> NAc and Amy

Question 4

BDNF in MDD brain areas

Answer 4

BDNF level:
- hipp: low
- PFC: low
- NAc: high
- Amy: high
- Thus the diverse roles of BDNF in depression depend on its location in the neural circuitry, namely, in the hippocampus and PFC BDNF inhibits depressive symptoms and whereas in the NAc and amygdala facilitates depression-like or anxiety-like symptoms
o This likely depends on the TrkB/p75 distribution and BDNF/pro-BDNF ratio
 pfc and hippo –> TrkB
 Nac and amyg –> p75

Question 5

BDNF level in MDD

Answer 5

• Various meta analyses show that peripheral (serum) and central (CSF) BDNF levels are lower in MDD patients (who received no antidepressant drug treatment) compared to healthy controls.
• Post-mortem brain samples (hippocampus, amygdala) of MDD patients also showed a reduction in BDNF mRNA and protein expression compared to healthy controls.
• Several SNPs of the BDNF gene have been associated with development of depression or suicide, most noteworthy the val66met SNP.
  o The substitution of valine by methionine leads to impaired processing of proBDNF to mBDNF and thereby limits activity-dependent release of BDNF
• Epigenetic studies have also shown increased methylation of BDNF promotor regions in depressed patients

Question 6

low BDNF in MDD

Answer 6

• From a neurobiological perspective however, a decrease in BDNF which impairs neuroplasticity, may partially explain the pathophysiology of MDD and thereby its symptomatology.
  o BDNF exerts its neurotrophic functions primarily through the TrkB receptor.
  o BDNF-TrkB signaling regulates neurogenesis, neuronal survival and synaptic plasticity (LTP), but can also directly result in increased neurotransmitter release.
  o A decrease in BDNF and subsequent impairment of TrkB activation may thus lead to reduced neuroplasticity.
• As currently understood, adult neurogenesis occurs in two areas; the subgranular zone (SGZ) of the dentate gyrus, and the subventricular zone (SVZ).
  o Hippocampal neurogenesis deficits in MDD are implicated by postmortem findings of decreases in hippocampal size and volume, in the number of neurons and glial cells, and in cell size.
  o The reduction in neurogenesis is plausible to be, in part, mediated by a decrease in BDNF levels.

Question 7

BDNF in antidepressant treatment

Answer 7

• According to the neurotrophic hypothesis depressive states might be due to a decreased expression of BDNF and therefore reduced neuroplasticity and functional disruptions of neural circuits.
• It further postulates that the effects of antidepressant drugs are mediated by the increase of BDNF expression and concentration leading to improved neuroplasticity in brain areas affected in depression
   Antidepressant-free depressed patients had lower BDNF concentrations than those of healthy and those of antidepressant-treated depressed patients
  –> tested in blood plasma fraction since it is also produced by platelets (blood=brain level???)
   BDNF concentration was negatively correlated with severity of depressive symptoms.
• SSRI/SNRI  Treatment for 2 months increased serum BDNF.
  o HT1A and HT2A receptor agonists lead to an upregulation of BDNF expression, leading to hippocampal neurogenesis, correlated with antidepressant response.
  o SSRI might act on TRKB receptor, leading to increased BDNF signalling and promoting neuronal plasticity/ antidepressant response.
  o Affinity of antidepressants to TrkB is low, but as antidepressants accumulate in brain, TrkB binding is achieved after several weeks of treatment. –> This might be the cause for slow action onset of typical antidepressants.
• Ketamine –> A rapid-acting antidepressant investigated was ketamine, an N-methyl-Daspartate receptor (NMDA-R) antagonist, which produces a fast reduction of depressive symptoms.
  o Ketamine seems to lead to an increase in synaptic BDNF levels in inhibitory interneurons such as in the hippocampus already after 4 hours due to the blockage of NMDA receptor.
  o It might also directly bind to TRKB.