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The Journal of Neuroscience, November 26, 2003, 23(34):10800-10808

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Development/Plasticity/Repair
Brain-Derived Neurotrophic Factor-Induced Gene Expression Reveals Novel Actions of VGF in Hippocampal Synaptic Plasticity

Janet Alder,^1 * Smita Thakker-Varia,^1 * Debra A. Bangasser,² May Kuroiwa,¹ Mark R. Plummer,³ Tracey J. Shors,² and Ira B. Black¹

¹Department of Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854-5635, ²Department of Psychology and Center for Collaborative Neuroscience, and ³Faculty of Arts and Sciences Division of Life Sciences, Nelson Laboratories, Rutgers University, Piscataway, New Jersey 08854

Synaptic strengthening induced by brain-derived neurotrophic factor (BDNF) is associated with learning and is coupled to transcriptional activation. However, identification of the spectrum of genes associated with BDNF-induced synaptic plasticity and the correlation of expression with learning paradigms in vivo has not yet been studied. Transcriptional analysis of BDNF-induced synaptic strengthening in cultured hippocampal neurons revealed increased expression of the immediate early genes (IEGs), c-fos, early growth response gene 1 (EGR1), activity-regulated cytoskeletal-associated protein (Arc) at 20 min, and the secreted peptide VGF (non-acronymic) protein precursor at 3 hr. The induced genes served as prototypes to decipher mechanisms of both BDNF-induced transcription and plasticity. BDNF-mediated gene expression was tyrosine kinase B and mitogen-activated protein kinase-dependent, as demonstrated by pharmacological studies. Single-cell transcriptional analysis of Arc after whole-cell patch-clamp recordings indicated that increased gene expression correlated with enhancement of synaptic transmission by BDNF. Increased expression in vitro predicted elevations in vivo: VGF and the IEGs increased after trace eyeblink conditioning, a hippocampal-dependent learning paradigm. VGF protein was also upregulated by BDNF treatment and was expressed in a punctate manner in dissociated hippocampal neurons. Collectively, these findings suggested that the VGF neuropeptides may regulate synaptic function. We found a novel function for VGF by applying VGF peptides to neurons. C-terminal VGF peptides acutely increased synaptic charge in a dose-dependent manner, whereas N-terminal peptide had no effect. These observations indicate that gene profiling in vitro can reveal new mechanisms of synaptic strengthening associated with learning and memory.

Key words: VGF; BDNF; synaptic plasticity; gene expression; hippocampus; learning

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Received Aug 11, 2003; revised September 22, 2003; accepted September 28, 2003.

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