The Neurotrophin-Inducible Gene Vgf Regulates Hippocampal Function and Behavior through a Brain-Derived Neurotrophic Factor-Dependent Mechanism
Journal of Neuroscience. 2008-09-24; 28(39): 9857-9869
DOI: 10.1523/jneurosci.3145-08.2008
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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.