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

Abstract

The neuropeptide VGF (non-acronymic) is induced by brain-derived neurotrophic factor and promotes hippocampal neurogenesis, as well as synaptic activity. However, morphological changes induced by VGF have not been elucidated. Developing hippocampal neurons were exposed to VGF through bath application or virus-mediated expression in vitro. VGF-derived peptide, TLQP-62, enhanced dendritic branching, and outgrowth. Furthermore, VGF increased dendritic spine density and the proportion of immature spines. Spine formation was associated with increased synaptic protein expression and co-localization of pre- and postsynaptic markers. Three non-synonymous single nucleotide polymorphisms (SNPs) were selected in human VGF gene. Transfection of N2a cells with plasmids containing these SNPs revealed no relative change in protein expression levels and normal protein size, except for a truncated protein from the premature stop codon, E525X. All three SNPs resulted in a lower proportion of N2a cells bearing neurites relative to wild-type VGF. Furthermore, all three mutations reduced the total length of dendrites in developing hippocampal neurons. Taken together, our results suggest VGF enhances dendritic maturation and that these effects can be altered by common mutations in the VGF gene. The findings may have implications for people suffering from psychiatric disease or other conditions who may have altered VGF levels.

Large-scale proteomic analysis of human prefrontal cortex identifies proteins associated with cognitive trajectory in advanced age

“…Our findings suggest that VGF likely act through mechanisms independent of amyloid plaques and neurofibrillary tangles in contributing to cognitive decline. VGF is a neuropeptide that promotes hippocampal neurogenesis, dendritic maturation, and synaptic activity 65 . VGF is induced by BDNF and serotonin and is upregulated by antidepressants, exercise, and is reduced in animal models of depression 66 .…”

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

“…Connectivity between hippocampus and vmPFC is sensitive to stress [45]. Thus parallel, stress-induced changes in VGF expression in the vmPFC and hippocampus may significantly contribute to the associated changes in volume and dendritic morphology that are observed in these two brain regions in stressed animals [46], and potentially could affect the connectivity between these regions as VGF C-terminal peptides TLQP-62 and AQEE-30, have been shown to potentiate synaptic transmission (21), promote dendritic maturation [47], and induce synaptogenesis (20). That ablation of VGF in either vmPFC (shown here) or dHc (shown previously in refs [10,48]) each increased sensitivity to stress or blocked rapid-acting antidepressant efficacy, is also suggestive that neural pathways connecting vmPFC and dHc, which could be impacted by either dHc or vmPFC manipulation, are critical to the actions of VGF in the regulation of depression-related behaviors.…”

“…Previous studies suggest that vmPFC dysfunction could result in abnormal stress responses [49]. VGF plays an indispensable role in the formation of secretory granules [50,51], the regulated release of neurotrophins and other growth factors [13], and the promotion of neuronal survival and dendritic outgrowth [47,52]. Reduced VGF levels could perhaps dysregulate neuronal homeostasis in the vmPFC, disrupting its normal function and increasing susceptibility to stress.…”

Identification of VGF nerve growth factor inducible-producing cells in human spinal cords and expression change in patients with amyotrophic lateral sclerosis

“…(VGF 588-617 ), and LQEQ-19 (VGF 599-617 ), and neuroendocrine regulatory peptides-1 (VGF 281-306 ) and -2 (VGF 310-347 ). These peptides are localized in neuronal and neuroendocrine cells in a tissue-specific manner [5][6][7] and exert specific neuronal bioactivities including an antidepressant effect, neurogenesis, and regulating energy expenditure [8][9][10][11].…”