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The Journal of Neuroscience, September 24, 2008, 28(39):9857-9869; doi:10.1523/JNEUROSCI.3145-08.2008

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Development/Plasticity/Repair
The Neurotrophin-Inducible Gene Vgf Regulates Hippocampal Function and Behavior through a Brain-Derived Neurotrophic Factor-Dependent Mechanism

Ozlem Bozdagi,¹ Erin Rich,¹ Sophie Tronel,¹ Masato Sadahiro,¹ Kamara Patterson,¹ Matthew L. Shapiro,^1,2 Cristina M. Alberini,¹ George W. Huntley,¹ and Stephen R. J. Salton^1,2

¹Departments of Neuroscience and ²Geriatrics, Mount Sinai School of Medicine, New York, New York 10029

Correspondence should be addressed to Dr. Stephen R. J. Salton, Department of Neuroscience, Box 1065, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029. Email: stephen.salton{at}mssm.edu

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.

Key words: BDNF; VGF; contextual fear conditioning; depression; LTD; LTP; neuropeptide; tPA

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Received June 27, 2008; revised Aug. 15, 2008; accepted Aug. 18, 2008.

Correspondence should be addressed to Dr. Stephen R. J. Salton, Department of Neuroscience, Box 1065, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029. Email: stephen.salton{at}mssm.edu

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