The neurotrophin-inducible gene Vgf regulates hippocampal function and behavior through a brain-derived neurotrophic factor-dependent mechanism

J Neurosci. 2008 Sep 24;28(39):9857-69. doi: 10.1523/JNEUROSCI.3145-08.2008.


VGF is a neurotrophin-inducible, activity-regulated gene product that is expressed in CNS and PNS neurons, in which it is processed into peptides and secreted. VGF synthesis is stimulated by BDNF, a critical regulator of hippocampal development and function, and two VGF C-terminal peptides increase synaptic activity in cultured hippocampal neurons. To assess VGF function in the hippocampus, we tested heterozygous and homozygous VGF knock-out mice in two different learning tasks, assessed long-term potentiation (LTP) and depression (LTD) in hippocampal slices from VGF mutant mice, and investigated how VGF C-terminal peptides modulate synaptic plasticity. Treatment of rat hippocampal slices with the VGF-derived peptide TLQP62 resulted in transient potentiation through a mechanism that was selectively blocked by the BDNF scavenger TrkB-Fc, the Trk tyrosine kinase inhibitor K252a (100 nm), and tPA STOP, an inhibitor of tissue plasminogen activator (tPA), an enzyme involved in pro-BDNF cleavage to BDNF, but was not blocked by the NMDA receptor antagonist APV, anti-p75(NTR) function-blocking antiserum, or previous tetanic stimulation. Although LTP was normal in slices from VGF knock-out mice, LTD could not be induced, and VGF mutant mice were impaired in hippocampal-dependent spatial learning and contextual fear conditioning tasks. Our studies indicate that the VGF C-terminal peptide TLQP62 modulates hippocampal synaptic transmission through a BDNF-dependent mechanism and that VGF deficiency in mice impacts synaptic plasticity and memory in addition to depressive behavior.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Behavior, Animal / physiology*
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Conditioning, Classical / physiology
  • Dose-Response Relationship, Radiation
  • Electric Stimulation / methods
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • Fear
  • Hippocampus / cytology*
  • In Vitro Techniques
  • Learning Disabilities / genetics
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / physiology*
  • Long-Term Potentiation / radiation effects
  • Male
  • Maze Learning / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation / physiology
  • Nerve Growth Factors
  • Neuropeptides / deficiency
  • Neuropeptides / physiology*
  • Patch-Clamp Techniques
  • Peptides / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Valine / analogs & derivatives
  • Valine / pharmacology


  • Brain-Derived Neurotrophic Factor
  • Enzyme Inhibitors
  • Excitatory Amino Acid Antagonists
  • Nerve Growth Factors
  • Neuropeptides
  • Peptides
  • Vgf protein, mouse
  • 2-amino-5-phosphopentanoic acid
  • Valine