The neurotrophin-inducible gene Vgf regulates hippocampal function and behavior through a brain-derived neurotrophic factor-dependent mechanism.
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.
Bozdagi
Ozlem
O
Department of Neuroscience, Mount Sinai School of Medicine, New York, New York 10029, USA.
Rich
Erin
E
Tronel
Sophie
S
Sadahiro
Masato
M
Patterson
Kamara
K
Shapiro
Matthew L
ML
Alberini
Cristina M
CM
Huntley
George W
GW
Salton
Stephen R J
SR
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D003214:Conditioning, Classical / Q000502:physiology; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005239:Fear; D006624:Hippocampus / Q000166:cytology*; D066298:In Vitro Techniques; D007859:Learning Disabilities / Q000235:genetics; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000502:physiology; D009414:Nerve Growth Factors; D009479:Neuropeptides / Q000172:deficiency / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D009414:Nerve Growth Factors; D009479:Neuropeptides; D010455:Peptides; C512697:Vgf protein, mouse; C056639:2-amino-5-phosphopentanoic acid; D014633:Valine