Cellular mechanism of absence epilepsy in calcium channel mutant mice

Homozygous tottering (tg) mice have a mutation in the voltage-dependent Cav2.1 (P/Q-type) calcium channel α1 2.1 subunit gene. tg mice show not only cerebellar ataxia but also absence epilepsy, which begins at about 3 weeks of age and persist throughout life. Similarities in EEG abnormality and in pharmacological sensitivity to antiepileptic drugs suggest that tg mice can serve as a model of human absence epilepsy. To identify the mechanism of epileptogenesis, I studied the effect of the calcium channel mutation on the thalamocortical network using whole-cell patch clamp recordings in brain slice preparations. The amplitude of inhibitory postsynaptic currents (IPSC) recorded from layer IV pyramidal cells of the cerebral cortex in response to thalamic stimulation became disproportionately reduced, compared with the amplitude of excitatory postsynaptic currents (EPSC), in the later developmental stage (P21-30). Similar results that the IPSC amplitude, but not the EPSC amplitude was drastically diminished were obtained by local stimulation in layer IV pyramidal neurons. However the reduction of the IPSC amplitude was not seen in layer V pyramidal neurons or in layer IV pyramidal neurons of younger tg mice before the onset of epilepsy (P14-16). Furthermore, recordings of multiple field potentials revealed that cortical excitation evoked by layer IV stimulation spread more widely in epileptic tg than in control or non-epileptic tg mice, although the area of excitation was confined within a barrel. These results demonstrated a close relationship between impaired IPSCs in layer IV and absence epilepsy, and suggested that the defect of the feed-forward inhibition in the cortical input layer is associated with the generation of absence epilepsy in tg mice