Proepileptic phenotype of SV2A-deficient mice is associated with reduced anticonvulsant efficacy of levetiracetam.

PURPOSE

Synaptic vesicle protein 2A (SV2A) constitutes a distinct binding site for an antiepileptic drug levetiracetam (Keppra). In the present study we characterized SV2A (+/-) heterozygous mice in several seizure models and tested if the anticonvulsant efficacy of levetiracetam is reduced in these mice.

METHODS

Seizure thresholds of male SV2A (+/-) mice and their wild-type littermates were assessed in pilocarpine (i.p.), kainic acid (s.c.), pentylenetetrazol (i.v.), 6-Hz and maximal electroshock models. Kindling development was compared in amygdala and corneal kindling models. Ex vivo binding of levetiracetam to SV2A was also performed.

RESULTS

Long-term electroencephalography (EEG) monitoring and behavioral observations of SV2A (+/-) mice did not reveal any spontaneous seizure activity. However, a reduced seizure threshold of SV2A (+/-) mice was observed in pilocarpine, kainic acid, pentylenetetrazol, and 6-Hz models, but not in maximal electroshock seizure model. Accelerated epileptogenesis development was also demonstrated in amygdala and corneal kindling models. Anticonvulsant efficacy of levetiracetam, defined as its ability to increase seizure threshold for 6 Hz electrical stimulation, was significantly reduced (approx. 50%) in the SV2A (+/-) mice, consistently with reduced binding to SV2A in these mice. In contrast, valproate produced the same anticonvulsant effect in both SV2A (+/+) and SV2A (+/-) mice.

DISCUSSION

The present results evidence that SV2A is involved in mediation of the in vivo anticonvulsant activity of levetiracetam, in accordance with its previously proposed mechanism of action. Furthermore, the present data also indicate that even partial SV2A deficiency may lead to increased seizure vulnerability and accelerated epileptogenesis.