Abstracts

SV2A is the most abundant isoform of SV2, a membrane glycoprotein common to all synaptic vesicles. This protein was recently reported (Lynch et al., PNAS 101:9861-66, 2004) to be the binding site of the newer generation antiepileptic drug, levetiracetam (Keppra^[reg]). The purpose of this study was to characterize the potential epilepsy-phenotype of mice lacking SV2A., SV2A KO mice were generated by using targeted gene disruption in S. Bajjalieh[apos]s laboratories at the University of Washington, Seattle (Crowder et al., PNAS 96:15268-73, 1999). Homozygous SV2A KO mice display severe seizures and are not viable beyond 2 weeks, thus precluding phenotyping in adults. In contrast, heterozygous SV2A KO mice (SV2A+/-) are viable. In this study, we compared SV2A+/- mice to wild type (WT) controls with respect to acute seizure susceptibility in response to both electrical and chemical stimulation. Evoked field potentials were recorded in the CA3, CA1 and DG areas of hippocampal slices [italic]in vitro[/italic]. Different groups of animals, aged 2 months, were used for each experiment., The electrical seizure threshold intensity inducing tonic hind limb extension after corneal electrode stimulation was comparable between SV2A+/- and WT mice (N=19-16/group). Similarly, there was no difference between SV2A+/- and WT mice in the threshold dose inducing generalized clonic seizures after continuous intravenous infusion of pentylenetetrazole (N=25/group). In contrast, the (stimulus intensity) [ndash] (population spike) curves of the field potentials recorded from hippocampal slices showed a higher excitability in the CA3 area in slices from SV2A+/- mice compared to WT controls. Likewise, kindling acquisition induced by twice daily corneal electrode stimulations (2 mA for 3 s) was markedly accelerated in SV2A+/- mice compared to WT (N=10/group). The induction of secondary generalized motor seizures in all SV2A+/- mice was reached after up to 12 repeated stimulations whereas up to 22 stimulations were necessary to reach this end point in WT mice., The results of this study suggest a key role of the SV2A protein in the establishment of a chronic epileptic condition, consonant with the seizure phenotype observed in SV2A homozygous mice. This supports that SV2A is the principal mechanism for the antiepileptic action of levetiracetam., (Supported by UCB S.A.)