Role of a VGF/BDNF/TrkB Autoregulatory Feedback Loop in Rapid-Acting Antidepressant Efficacy

Abstract

Members of the neurotrophin family and in particular brain-derived neurotrophic factor (BDNF) regulate the response to rapid- and slow-acting chemical antidepressants and voluntary exercise. Recent work suggests that rapid-acting antidepressants that modulate N-methyl-D-aspartate receptor (NMDA-R) signaling (e.g., ketamine and GLYX-13) require expression of VGF (non-acronymic), the BDNF-inducible secreted neuronal protein and peptide precursor, for efficacy. In addition, the VGF-derived C-terminal peptide TLQP-62 (named by its 4 N-terminal amino acids and length) has antidepressant efficacy following icv or intra-hippocampal administration, in the forced swim test (FST). Similar to ketamine, the rapid antidepressant actions of TLQP-62 require BDNF expression, mTOR activation (rapamycin-sensitive), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activation (NBQX-sensitive) and are associated with GluR1 insertion. We review recent findings that identify a rapidly induced autoregulatory feedback loop, which likely plays a critical role in sustained efficacy of rapid-acting antidepressants, depression-like behavior, and cognition, and requires VGF, its C-terminal peptide TLQP-62, BDNF/TrkB signaling, the mTOR pathway, and AMPA receptor activation and insertion.

Dietary Supplementation with Fish Oil or Conjugated Linoleic Acid Relieves Depression Markers in Mice by Modulation of the Nrf2 Pathway

“…Given the decrease of BDNF in depression pathogenesis, we next decided to evaluate whether Old mice exhibited lower amount of this neurotrophin. The results show an age‐associated decline of BDNF in brain homogenates of Old MRL/lpr (about 1.8‐fold, p < 0.01) as evidenced by immunoblotting analysis ( Figure A).…”

“…Beside behavioral signs, activation of inflammatory/oxidative stress pathways, alteration of brain n‐6/n‐3 PUFA ratio, and MUFA/SFA content (e.g., DHA; C22:6 n‐3, Oleic, C18:1; Palmitic, C16:0; stearic acid, C18:0) underlie pathology onset and progression. In addition, several parameters involved in brain functioning (brain‐derived neurotrophic factor, BDNF; Tropomyosin receptor kinase B receptor, TrkB), synaptic transmission, and cholinergic signaling (acetylcholinesterase activity, AChE) have been associated with depression pathogenesis.…”

VGF and its C-terminal peptide TLQP-62 in ventromedial prefrontal cortex regulate depression-related behaviors and the response to ketamine

“…Could the antidepressant actions of intra-vmPFC TLQP-62 also be dependent on BDNF trafficking and secretion in this region? Previous studies strongly suggest that TLQP-62 may be a critical component of a positive autoregulatory feedback loop that potentiates local BDNF synthesis and secretion and BDNF/TrkB signaling [60], regulating depressionrelated behaviors and memory. Moreover, we found that local BDNF knockdown abolishes increased GluR1 levels in vmPFC synaptosomes 8 days after TLQP-62 infusion.…”

“…We propose that VGF and its C-terminal peptide TLQP-62 in the vmPFC potentially increase intracellular Ca 2+ levels via IP 3 -mediated Ca 2+ release from ER, and/or via Ca 2+ influx mediated by SOCE and/or TRPC mechanisms, which subsequently stimulate BDNF secretion. This promotes BDNF/TrkB signaling and mTOR pathway activation, resulting in increased expression and phosphorylation (Ser845) of GluR1, stimulating synaptic trafficking of GluR1 and GluR1dependent synaptic potentiation [58], thus regulating depressionrelated behaviors and the response to ketamine [10,60].…”

Understanding depression: the hippocampus might hold the answer in a CREB‐regulated transcription coactivator

“…But also, increased hippocampal BDNF and VGF seemingly play a crucial role the rapid anti‐depressant effects of ketamine (Jiang et al . ). Perhaps future studies using this model of hippocampal CRTC1 modulation will investigate the anti‐depressive effects of ketamine.…”