Reduction of vesicle-associated membrane protein 2 expression leads to a kindling-resistant phenotype in a murine model of epilepsy

E. A. Matveeva, D. A. Price, S. W. Whiteheart, T. C. Vanaman, G. A. Gerhardt, J. T. Slevin

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Our previous work has correlated permanent alterations in the rat neurosecretory machinery with epileptogenesis. Such findings highlighted the need for a greater understanding of the molecular mechanisms underlying epilepsy so that novel therapeutic regimens can be designed. To this end, we examined kindling in transgenic mice with a defined reduction of a key element of the neurosecretory machinery: the v-SNARE (vesicle-bound SNAP [soluble NSF attachment protein] receptor), synaptobrevin/vesicle-associated membrane protein 2 (VAMP2). Initial analysis of biochemical markers, which previously displayed kindling-dependent alterations in rat hippocampal synaptosomes, showed similar trends in both wild-type and VAMP2 +/- mice, demonstrating that kindled rat and mouse models are comparable. This report focuses on the effects that a ~50% reduction of synaptosomal VAMP2 has on the progression of electrical kindling and on glutamate release in hippocampal subregions. Our studies show that epileptogenesis is dramatically attenuated in VAMP2 +/- mice, requiring both higher current and more stimulations to reach a fully kindled state (two successive Racine stage 5 seizures). Progression through the five identifiable Racine stages was slower and more variable in the VAMP2 +/- animals compared with the almost linear progression seen in wild-type littermates. Consistent with the expected effects of reducing a major neuronal v-SNARE, glutamate-selective, microelectrode array (MEA) measurements in specific hippocampal subregions of VAMP2 +/- mice showed significant reductions in potassium-evoked glutamate release. Taken together these studies demonstrate that manipulating the levels of the neurosecretory machinery not only affects neurotransmitter release but also mitigates kindling-induced epileptogenesis.

Original languageEnglish
Pages (from-to)77-86
Number of pages10
JournalNeuroscience
Volume202
DOIs
StatePublished - Jan 27 2012

Bibliographical note

Funding Information:
We acknowledge the technical assistance of Ramona Alcala and Verda A. Davis. This work is supported by the Department of Veterans Affairs (J.T.S.), Defense Advanced Research Projects Agency ( N66001-09-C-2080 ) (G.G.), and the National Institutes of Health ( HL56652 and HL091893 ) (S.W.W.).

Keywords

  • Epileptogenesis
  • Glutamate
  • Hippocampus
  • Kindling
  • SNARE

ASJC Scopus subject areas

  • Neuroscience (all)

Fingerprint

Dive into the research topics of 'Reduction of vesicle-associated membrane protein 2 expression leads to a kindling-resistant phenotype in a murine model of epilepsy'. Together they form a unique fingerprint.

Cite this