Function of synaptic vesicle protein 2A (SV2A) as a novel therapeutic target for epilepsy

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  • Tokudome Kentaro
    Department of Pharmacology, Osaka University of Pharmaceutical Sciences
  • Shimizu Saki
    Department of Pharmacology, Osaka University of Pharmaceutical Sciences
  • Serikawa Tadao
    Department of Pharmacology, Osaka University of Pharmaceutical Sciences
  • Ohno Yukihiro
    Department of Pharmacology, Osaka University of Pharmaceutical Sciences

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  • 新たなてんかん治療標的分子synaptic vesicle protein 2A（SV2A）の機能解析
  • アラタ ナ テンカン チリョウ ヒョウテキ ブンシ synaptic vesicle protein 2A (SV2A)ノ キノウ カイセキ

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Abstract

<p>Epilepsy is a chronic neurologic disease characterized by recurrent seizures, affecting nearly 1% of the population. Synaptic vesicle protein 2A (SV2A) is a membrane protein specifically expressed in synaptic vesicles and is now implicated in the pathogenesis of epileptic disorders. This is because 1) Sv2a-knockout mice exhibit severe seizures, 2) SV2A serves as a specific binding site for certain antiepileptics (e.g., levetiracetam and its analogues) and 3) the SV2A expression changes under various epileptic conditions both in animals (e.g., kindling) and humans (e.g., intractable temporal lobe epilepsy and focal cortical dysplasia). Furthermore, it has been shown that a missense mutation in the SV2A gene caused intractable epilepsy, involuntary movements and developmental retardation, indicating a causative role of SV2A dysfunction in epilepsy. In order to explore the mechanism of SV2A in modulating development of epileptogenesis, we recently developed a novel rat model (Sv2aL174Q rat) carrying a missense mutation (Leu174Gln) in the Sv2a gene. These rats were highly susceptible to the kindling development associated with repeated pentylenetetrazole treatments or electrical stimulations of the amygdala. In addition, the Sv2aL174Q mutation specifically impaired depolarization-induced GABA, but not glutamate, release in the hippocampus and amygdala. All this evidence indicates that the SV2A-GABAergic system plays a crucial role in modulating epileptogenesis and encourages discovery research into the novel antiepileptic agents which enhance the function of the SV2A-GABA system.</p>

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