Generation of epilepsy model animal bearing a genetic abnormality identified in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) of human

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Mutations of genes encoding α4, 2 or α2 subunits (CHRNA4, CHRNB2, or CHRNA2, respectively) of neuronal nicotinic ACh receptor nAChR) cause nocturnal frontal lobe epilepsy (NFLE) in human. NFLE-related seizures are seen exclusively during sleep and are characterized by three distinct seizure phenotypes : "paroxysmal arousals," "paroxysmal dystonia," and "episodic wandering." We generated transgenic rat strains that harbor a missense mutation S284L, which had been identified in CHRNA4 in NFLE. The transgenic rats were free of biological abnormalities, such as dysmorphology in the CNS, and behavioral abnormalities. The transgenic rats showed epileptic seizure phenotypes during slow-wave sleep (SWS) similar to those in NFLE exhibiting three characteristic seizure phenotypes and thus fulfilled the diagnostic criteria of human NFLE. The rats exhibited two major abnormalities in neurotransmission : (1) enhanced AMPA/glutamatergic excitatory transmission in focus region and (2) abnormal glutamate release during SWS. The currently available genetically engineered animal models of epilepsy are limited to mice ; thus, our transgenic rats offer another dimension to the epilepsy research field.