202308041446

Brain-derived neurotrophic factor: BDNF is a growth factor involved in synaptic plasticity. Release of BDNF is associated with neural health, dendritic growth and branching, and synaptogenesis. Also involved in LTP.

Expression

• Widely distributed throughout CNS and PNS
• PFC, Hippocampus, amygdala, Nucleus accumbens

Synthesis

• Synthesized as pre-proBDNF in endoplasmic reticulum.
• Transported to Golgi apparatus where it’s cleaved into proBDNF.
• proBDNF is transformed into mBDNF (mature)

BDNF vs. pro-BDNF

• BDNF mediates cell survival, branching, etc. via tropomysin receptor kinase type B (TrkB), recruiting Ras-Raf-MEK, PI3 kinase, PLCy signaling pathways
  • Growth, survival, plasticity
• proBDNF binds to sortilin & p75 neurotrophin receptors, modulates NF-kB, JNK, RhoGTPase and ceramide signaling pathways
  • Cell death, apoptosis
    
    

Val66Met

• Polymorphism indicating amino acid change at codon 66, lying in the pro-domain of BDNF. Met allele is a loss of function allele, causing decreased expression of BDNF and blocking activity-dependent release of protein.

Signaling Cascades

1. AKT (PI3K cascade) requires activation of PI3K enzyme to catalyse reaction, resulting in dendritic growth
2. RAS pathway (MAPK/Erk) is activated during neuronal differentiation and synapse formation
3. PLC-y cascade is related to neuroplasticity enhancement through increased secretion of $C{a}^{2+}$.
   

Regional Differences

Hippocampus

• Decreased amounts of BDNF and increased amounts of proBDNF associated with neuronal atrophy, apoptosis, and associated with MDD and chronic stress
  • Reversed by antidepressants and ECT
• Decreased ability of hippocampus to inhibit HPA axis via Cortisol.

Prefrontal Cortex

• Volumetric changes in PFC in depression resulting from decreased TrkB/BDNF binding.
• Decreased ability to inhibit HPA axis.

Nucleus accumbens

• Increased BDNF/TrkB expression in NAc and VTA in depression, resulting in overactivation of the reward circuit & subsequent desensitization (leading to anhedonia)

Amygdala

• Overexpression of BDNF/TrkB, underexpression of proBDNF/p75 results in overactivation of AMY, increased BLA spine density, increase in anxiety-like behavior
• Increased ability of amygdala to activate HPA axis upon stressors.

Serum/Plasma Levels

• Negative correlation b/w severity of depressive symptoms and BDNF levels
• BDNF in periphery comes from platelets, which can be detected in serum → decreased in depression patients.
• Antidepressant treatment increases serum BDNF.
• BDNF can be hardly measured in plasma because significantly less, but plasma analysis shows free-fraction. Not significant evidence for role of plasma BDNF in depression.

Antidepressants

• Require BDNF for efficacy due to necessity of BDNF in restoring HPA axis functionality and morphology and activity of hippocampus, prefrontal cortex, amygdala, and NAc.