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The Journal of Neuroscience, September 28, 2005, 25(39):8889-8897; doi:10.1523/JNEUROSCI.2577-05.2005
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Neurobiology of Disease
Depression of Synaptic Transmission by Vascular Endothelial Growth Factor in Adult Rat Hippocampus and Evidence for Increased Efficacy after Chronic Seizures
Daniel P. McCloskey,1 Susan D. Croll,2,3,4 andHelen E. Scharfman1,5 1Center for Neural Recovery and Rehabilitation Research, Helen Hayes Hospital, West Haverstraw, New York 10993, 2Department of Psychology, and Neuropsychology and Neuroscience Doctoral Subprograms, Queens College, Flushing, New York 11367, 3Graduate Center of City University of New York, New York, New York 10016, 4Regeneron Pharmaceuticals, Tarrytown, New York 10591, and 5Departments of Pharmacology and Neurology, Columbia University, College of Physicians and Surgeons, New York, New York 10032
In addition to its potent effects on vasculature, it has become clear that vascular endothelial growth factor (VEGF) has effects on both neurons and glia, and recent studies suggest that it can be neuroprotective. To determine potential mechanisms underlying this neuroprotection, recombinant human VEGF was bath applied to adult rat hippocampal slices, and both extracellular and intracellular recordings were used to examine intrinsic properties and synaptic responses of hippocampal principal neurons. Initial studies in area CA1 showed that VEGF significantly reduced the amplitude of responses elicited by Schaffer collateral stimulation, without influencing membrane properties. Similar effects occurred in CA3 pyramidal cells and dentate gyrus granule cells when their major glutamatergic afferents were stimulated. Because VEGF expression is increased after seizures, effects of VEGF were also examined in rats with recurrent spontaneous seizures. VEGF reduced spontaneous discharges in slices from these rats but had surprisingly little effect on epileptiform discharges produced by disinhibition of slices from control rats. These results demonstrate a previously unknown effect of VEGF on neuronal activity and also demonstrate a remarkable potency in the epileptic brain. Based on this, we suggest that VEGF or VEGF-related targets could provide useful endpoints to direct novel therapeutic strategies for epilepsy.
Key words: anticonvulsant; hippocampus; intracellular; neuromodulation; synaptic transmission; VEGF
Received June 22, 2005; revised August 15, 2005; accepted August 17, 2005.
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