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

Abstract

Patients with major depressive disorder (MDD) often have structural and functional deficits in the ventromedial prefrontal cortex (vmPFC), but the underlying molecular pathways are incompletely understood. The neuropeptide precursor VGF (non-acronymic) plays a critical role in depression and antidepressant efficacy in hippocampus and nucleus accumbens, however its function in vmPFC has not been investigated. Here, we show that VGF levels were reduced in Brodmann area 25 (a portion of human vmPFC) of MDD patients and in mouse vmPFC following chronic restraint stress (CRS), and were increased by ketamine in mouse vmPFC. VGF overexpression in vmPFC prevented behavioral deficits induced by CRS, and VGF knockdown in vmPFC increased susceptibility to subchronic variable stress (SCVS) and reduced ketamine's antidepressant efficacy. Acute intra-vmPFC TLQP-62 infusion induced behavioral phenotypes that mimic those produced by antidepressant drug treatment. These antidepressant-like effects were sustained for 7 days and were abolished by local Bdnf gene ablation, or pretreatment with xestospongin C, an inhibitor of IP 3mediated Ca 2+ release, or SKF96365, an inhibitor of store-operated and TRPC channel-mediated Ca 2+ entry. In conclusion, VGF in the vmPFC regulates susceptibility to stress and the antidepressant response to ketamine. TLQP-62 infusion produces sustained antidepressant responses that require BDNF expression and calcium mobilization in vmPFC.

CIC is a critical regulator of neuronal differentiation

“…Derepressed VGF expression from the deep layer may have functions separate from CIC-mediated neuronal differentiation and maturation. Corroborating this possibility, a recent study demonstrated that VGF has a critical role in mood regulation (37,38).…”

VGF-derived peptide TLQP-21 modulates microglial function through C3aR1 signaling pathways and reduces neuropathology in 5xFAD mice

“…The Vgf (non-acronymic) gene encodes a neuronal and neuroendocrine protein precursor [1] that is posttranslationally processed with cell-and tissue-type specificity into multiple bioactive peptides that are secreted and are involved in numerous physio/pathological functions including reproduction [2], depression [3,4], obesity [5], memory [6] and also neurodegenerative diseases, in particular Alzheimer's disease (AD). In AD patients, VGF-derived peptides are reduced in the cerebrospinal fluid (CSF), suggesting their potential utility as biomarkers and a possible role for VGF in AD pathogenesis and progression [7][8][9][10][11][12][13][14].…”

Targeting the Neuronal Activity of Prefrontal Cortex: New Directions for the Therapy of Depression

“…The neuropeptide precursor VGF plays a pivotal role in the etiology of depression and antidepressant action [ 66 ]. Research studies have shown that the levels of VGF were decreased in BA25 (a part of human vmPFC) of MDD individuals and in the vmPFC of mice which experienced CRS training, while they were elevated by ketamine in mice vmPFC [ 66 ].…”

“…The neuropeptide precursor VGF plays a pivotal role in the etiology of depression and antidepressant action [ 66 ]. Research studies have shown that the levels of VGF were decreased in BA25 (a part of human vmPFC) of MDD individuals and in the vmPFC of mice which experienced CRS training, while they were elevated by ketamine in mice vmPFC [ 66 ]. The overexpression of VGF in vmPFC rescued behavioral deficits induced by CRS, and the knockdown of VGF in vmPFC increased the susceptibility to subchronic variable stress (SCVS) and inhibited the antidepressant efficacy of ketamine [ 66 ].…”