VGF and its C-terminal peptide TLQP-62 regulate memory formation in hippocampus via a BDNF-TrkB-dependent mechanism

Wei Jye Lin, Cheng Jiang, Masato Sadahiro, Ozlem Bozdagi, Lucy Vulchanova, Cristina M. Alberini, Stephen R. Salton

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)10343-10356
Number of pages14
JournalJournal of Neuroscience
Volume35
Issue number28
DOIs
StatePublished - Jul 15 2015

Keywords

  • BDNF
  • Memory
  • Rac1
  • TLQP-62
  • TrkB
  • VGF

ASJC Scopus subject areas

  • Neuroscience(all)

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