Abstracts

Synaptic vesicle protein 2A (SV2A) was recently identified as the specific binding site for levetiracetam in the brain and as a promising target for drug development. We have previously reported the differential expression of SV2A in the neocortex of patients with cortical dysplasia (CD)-associated pharmacoresistant epilepsy (Alexopoulos et al., Epilepsia 46 Suppl. 8:273, 2005).
The objective of this study is to investigate the expression of the same protein in a well-characterized animal model of CD., Sprague-Dawley time-pregnant rats received 145cGy whole body irradiation at embryonic day 17, resulting in pups with multifocal hippocampal (HIP) and cortical abnormalities. These animals exhibit recurrent, spontaneous seizures following [ldquo]a second hit[rdquo] in the form of a single dose of pentylenetetrazol (PTZ 30mg/kg i.p.; postnatal day 60). Occurrence of seizures was confirmed by video-EEG and behavioral monitoring.
Age-matched, nonirradiated controls received the same subconvulsive dose of PTZ. Video-EEG recordings were obtained for 1 month before and after PTZ injection in all animals.
Brains were examined using Cresyl Violet and immunostaining for SV2A and neuron-specific nuclear protein., Irradiated rats (n=8), but not control rats (n=3) developed spontaneous behavioral and electrographic seizures following PTZ ([quot]second hit[quot]), characterized by extended periods of arrest, facial or forelimb clonus and occasionally rearing and falling.
Immunocytochemical (ICC) analysis in the cortex and HIP of non-irradiated controls showed SV2A to be localized in regions surrounding cell bodies. Punctate staining was observed in HIP areas occupied by mossy fiber terminals.
Histological examination of stained slices of irradiated animals confirmed the presence of multifocal CD and neuronal dispersion in HIP. ICC analysis of irradiated epileptic animals displayed a redistribution of the SV2A protein from the cell bodies to the neuropil (figure 1). SV2A in HIP of irradiated rats occupied the area of the hilus and apical dendrites in the dentate gyrus and cornus ammonis., The differential changes in SV2A immunoreactivity following recurrent seizures in dysplastic but not control animals are reminiscent of those observed in human epileptic and dysplastic tissue. Further studies will examine the influence of seizures in the SV2A redistribution, and its potential role in the expression of epileptogenesis and pharmacoresistance.[figure1], (Supported by Investigator-initiated study grant to A.V.A. sponsored by UCB, Inc.)