Deletion of phospholipase C beta4 in thalamocortical relay nucleus leads to absence seizures.

Absence seizures are characterized by cortical spike-wave discharges (SWDs) on electroencephalography, often accompanied by a shift in the firing pattern of thalamocortical (TC) neurons from tonic to burst firing driven by T-type Ca(2+) currents. We recently demonstrated that the phospholipase C beta4 (PLCbeta4) pathway tunes the firing mode of TC neurons via the simultaneous regulation of T- and L-type Ca(2+) currents, which prompted us to investigate the contribution of TC firing modes to absence seizures. PLCbeta4-deficient TC neurons were readily shifted to the oscillatory burst firing mode after a slight hyperpolarization of membrane potential. TC-limited knockdown as well as whole-animal knockout of PLCbeta4 induced spontaneous SWDs with simultaneous behavioral arrests and increased the susceptibility to drug-induced SWDs, indicating that the deletion of thalamic PLCbeta4 leads to the genesis of absence seizures. The SWDs were effectively suppressed by thalamic infusion of a T-type, but not an L-type, Ca(2+) channel blocker. These results reveal a primary role of TC neurons in the genesis of absence seizures and provide strong evidence that an alteration of the firing property of TC neurons is sufficient to generate absence seizures. Our study presents PLCbeta4-deficient mice as a potential animal model for absence seizures.