The Neuropeptide VGF Is Reduced in Human Bipolar Postmortem Brain and Contributes to Some of the Behavioral and Molecular Effects of Lithium

Abstract

Recent studies demonstrate that the neuropeptide VGF (nonacronymic) is regulated in the hippocampus by antidepressant therapies and animal models of depression and that acute VGF treatment has antidepressant-like activity in animal paradigms. However, the role of VGF in human psychiatric disorders is unknown. We now demonstrate using in situ hybridization that VGF is downregulated in bipolar disorder in the CA region of the hippocampus and Brodmann's area 9 of the prefrontal cortex. The mechanism of VGF in relation to LiCl was explored. Both LiCl intraperitoneally and VGF intracerebroventricularly reduced latency to drink in novelty-induced hypophagia, and LiCl was not effective in VGF ϩ/Ϫ mice, suggesting that VGF may contribute to the effects of LiCl in this behavioral procedure that responds to chronic antidepressant treatment. VGF by intrahippocampal injection also had novel activity in an amphetamine-induced hyperlocomotion assay, thus mimicking the actions of LiCl injected intraperitoneally in a system that phenocopies manic-like behavior. Moreover, VGF ϩ/Ϫ mice exhibited increased locomotion after amphetamine treatment and did not respond to LiCl, suggesting that VGF is required for the effects of LiCl in curbing the response to amphetamine. Finally, VGF delivered intracerebroventricularly in vivo activated the same signaling pathways as LiCl and is necessary for the induction of mitogen-activated protein kinase and Akt by LiCl, thus lending insight into the molecular mechanisms underlying the actions of VGF. The dysregulation of VGF in bipolar disorder as well as the behavioral effects of the neuropeptide similar to LiCl suggests that VGF may underlie the pathophysiology of bipolar disorder.

Neuropeptide VGF Promotes Maturation of Hippocampal Dendrites That Is Reduced by Single Nucleotide Polymorphisms

“…Parallel to BDNF, TLQP-62’s behavioral actions are also mediated by the PI3K/Akt/mTOR pathway, supporting the notion that VGF is upstream of BDNF signaling [1,26]. Moreover, VGF has been shown to be required for the biochemical and behavioral effects of antidepressants [27]. …”

“…VGF-derived peptides increase adult neurogenesis in the dentate gyrus [23,27,37,38] and has neuroprotective effects in injured neurons to promote cell survival [39,40]. Studies have shown that neuropeptides are among the many endogenous factors that play a role in reorganizing neuronal networks by modulating neuronal activity [41].…”

Wnt/β-catenin signaling regulates Dental Pulp Stem Cells’ responses to pulp injury by resinous monomers

“…indirect, through GSK3␤ inhibition vs. direct through receptor/ligand binding). Indeed, LiCl, a drug commonly used to treat bipolar disease [34], is a widely used activator of Wnt/␤-catenin signaling via inhibition of GSK3␤, which abrogates ␤-catenin phosphorylation and its degradation by the proteasomes [35]. On the other hand, Wnt-1 is known to act through direct binding to the frizzled receptor and LRP6 co-receptor leading to TCF/LEF activation through ␤-catenin stabilization [36].…”

VGF: An inducible gene product, precursor of a diverse array of neuro-endocrine peptides and tissue-specific disease biomarkers

“…In human brain cortex, a reduction of human VGF C-terminus, Nterminus, and/or PGH and NERP-1 peptides was suggested in cases of Alzheimer's and Parkinson's disease, with a degree of selective change between the two conditions . In human bipolar disorder, VGF mRNA was found to be downregulated in the CA region of the hippocampus and Brodmann's area 9 of the prefrontal cortex (Thakker-Varia et al, 2010). In cases of sporadic amyotrophic lateral sclerosis (ALS), VGF immunoreactivity was found to be severely reduced in spinal motor neurons (Shimazawa et al, 2010).…”