VGF and Its C-Terminal Peptide TLQP-62 Regulate Memory Formation in Hippocampus via a BDNF-TrkB-Dependent Mechanism

Abstract

Regulated expression and secretion of BDNF, which activates TrkB receptor signaling, is known to play a critical role in cognition. Identification of additional modulators of cognitive behavior that regulate activity-dependent BDNF secretion and/or potentiate TrkB receptor signaling would therefore be of considerable interest. In this study, we show in the adult mouse hippocampus that expression of the granin family gene Vgf and secretion of its C-terminal VGF-derived peptide TLQP-62 are required for fear memory formation. We found that hippocampal VGF expression and TLQP-62 levels were transiently induced after fear memory training and that sequestering secreted TLQP-62 peptide in the hippocampus immediately after training impaired memory formation. Reduced VGF expression was found to impair learning-evoked Rac1 induction and phosphorylation of the synaptic plasticity markers cofilin and synapsin in the adult mouse hippocampus. Moreover, TLQP-62 induced acute, transient activation of the TrkB receptor and subsequent CREB phosphorylation in hippocampal slice preparations and its administration immediately after training enhanced long-term memory formation. A critical role of BDNF-TrkB signaling as a downstream effector in VGF/TLQP-62-mediated memory consolidation was further revealed by posttraining activation of BDNF-TrkB signaling, which rescued impaired fear memory resulting from hippocampal administration of anti-VGF antibodies or germline VGF ablation in mice. We propose that VGF is a critical component of a positive BDNF-TrkB regulatory loop and, upon its induced expression by memory training, the TLQP-62 peptide rapidly reinforces BDNF-TrkB signaling, regulating hippocampal memory consolidation.

Role of Hypothalamic VGF in Energy Balance and Metabolic Adaption to Environmental Enrichment in Mice

“…98% C57BL/6J background; MAX-BAX; Charles River Laboratories) were provided by Dr S. Salton of Icahn School of Medicine at Mount Sinai. Vgf gene targeting in VGF flpflox/flpflox mice has recently been described (34); the entire Vgf coding sequence is flanked by 5 0 and 3 0 loxP sites, and the pgk-neo selection cassette in the Vgf 3 0 untranslated region was excised in this line. All mice were housed in temperature (22°C-23°C) and humidity controlled rooms with a 12-hour light, 12-hour dark cycle, and maintained on a standard rodent diet (7912 rodent chow; Teklad) with food and water ad libitum.…”

“…Taken together, our results suggest hypothalamic VGF responds to environmental demands and plays an important role in energy balance and glycemic control likely acting in the melanocortin pathway downstream of BDNF. (Endocrinology 2016: [34][35][36][37][38][39][40][41][42][43][44][45][46]2016) I n 2014, 52% of adults worldwide were overweight or obese, thus this epidemic has undoubtedly become a global health, social, and economic problem (1,2). Substantial obesity-related morbidity and mortality have prompted many investigations to explore genes involved in metabolic regulation.…”

“…Foglesong et al Role of Hypothalamic VGF in Energy Balance Endocrinology, January 2016, 2016(1): [34][35][36][37][38][39][40][41][42][43][44][45][46] BDNF, leptin, and MC4R agonist on hypothalamic Vgf expression. Direct injection of BDNF protein to the hypothalamus decreased weight gain (PBS, -1.517 6 0.323 g and BDNF, -2.767 6 0.165 g; P = 0.02) with no significant effect on food intake (PBS, 1.517 6 0.409 g and BDNF, 1.567 6 0.308 g; P = 0.91) and significantly upregulated the expression of Vgf, Mc4r, and Npy (encoding neuropeptide Y) ( Figure 1E).…”

“…Foglesong et al Role of Hypothalamic VGF in Energy Balance Endocrinology, January 2016, 2016(1): [34][35][36][37][38][39][40][41][42][43][44][45][46] with the following characteristics: increase of adiposity; lower core body temperature; impaired glucose tolerance; decrease of energy expenditure without change of food intake; elevated levels of leptin, cholesterol, and fatty acid in circulation; "whitening" of BAT; and suppression of the expression of genes involved in lipid metabolism and glucose metabolism in WAT. This phenotype of hypothalamic knockdown was mostly opposite to the germline global knockout mice (22) but instead largely consistent to the functions of a VGF-derived peptide TLQP-21 observed in the adult animals (28).…”

The Pathways Involved in TLQP-62 Mediated Biological Functions

“…Other behavioral and physiological roles of this neuropeptide includes the following: stimulation of insulin secretion in insulinoma cells, regulation of gene expression in INS1E cells, activation of the intracellular signaling pathways, enhancement of intracellular calcium mobilization in INS1E cells, trophic and proliferative effects on insulinoma cell lines, in the act of improving glucose tolerance in vivo, determination of phases of neurogenesis, enhancing synaptic activity [4][5][6].…”