title: Reduction of vesicle-associated membrane protein 2 expression leads to a kindling-resistant phenotype in a murine model of epilepsy.
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.
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky Medical Center, Lexington, KY, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Matveeva
authors.forename: D A
authors.initials: DA
authors.lastname: Price
authors.forename: S W
authors.initials: SW
authors.lastname: Whiteheart
authors.forename: T C
authors.initials: TC
authors.lastname: Vanaman
authors.forename: G A
authors.initials: GA
authors.lastname: Gerhardt
authors.forename: J T
authors.initials: JT
authors.lastname: Slevin
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism; D056651:CA2 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism; D003627:Data Interpretation, Statistical; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism; D004558:Electric Stimulation; D004827:Epilepsy / Q000503:physiopathology*; D018698:Glutamic Acid / Q000378:metabolism; D007696:Kindling, Neurologic / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008839:Microelectrodes; D050600:SNARE Proteins / Q000502:physiology; D050988:Vesicle-Associated Membrane Protein 2 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*
chemical_list: D050600:SNARE Proteins; D050988:Vesicle-Associated Membrane Protein 2; C494808:vesicle-associated membrane protein 2, mouse; D018698:Glutamic Acid