Yukihiro Ohno* and Kentaro Tokudome Pages 463 - 471 ( 9 )
Dysfunction of synaptic neurotransmitter release is closely involved in the pathogenesis of various central nervous system diseases. Synaptic vesicle glycoprotein 2A (SV2A) is a membrane protein specifically expressed in synaptic vesicles and it modulates action potential-dependent neurotransmitter release in the brain. Since 1) SV2A-knockout mice exhibit severe convulsive seizures, 2) SV2A expression in the brain is reportedly altered in various epileptic disorders both in animal models (e.g., kindling and genetic models) and humans (e.g., intractable temporal lobe epilepsy and focal cortical dysplasia) and 3) SV2A serves as a specific binding site for the antiepileptic drug, levetiracetam and its analogues, it is considered that SV2A is involved in the pathogenesis and treatment of epilepsy. In addition, a recent clinical study demonstrated that a missense mutation in the SV2A gene caused intractable epilepsy with involuntary movements and developmental retardation, illustrating a causative role of SV2A dysfunction in epilepsy. Although the functional mechanisms of SV2A in regulating epileptogenesis remain unknown, studies using animals carrying the Sv2a missense mutation showed that the dysfunction of SV2A preferentially disrupts action potential-induced γ-aminiobutyric acid (GABA), but not glutamate, released in the limbic regions (i.e., hippocampus and amygdala) and markedly facilitates kindling epileptogenesis. All these evidences indicate that the SV2A-GABAergic system plays a crucial role in modulating epileptogenesis and encourages research on the novel antiepileptic agents which enhance SV2A function.
Antiepileptic drugs, epilepsy, epileptogenesis, γ-aminiobutyric acid, glutamate, neurotransmitter release, synaptic vesicle glycoprotein 2A.
Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569- 1094