Neurons of the reticular thalamus (RT) display oscillatory burst discharges that are believed to be critical for thalamocortical network oscillations related to absence epilepsy. Ca²+-dependent mechanisms underlie such oscillatory discharges. However, involvement of high-voltage activated (HVA) Ca²+ channels in this process has been discounted. We examined this issue closely using mice deficient for the HVA Ca(v)2.3 channels. In brain slices of Ca(v)2.3⁻/⁻, a hyperpolarizing current injection initiated a low-threshold burst of spikes in RT neurons; however, subsequent oscillatory burst discharges were severely suppressed, with a significantly reduced slow afterhyperpolarization (AHP). Consequently, the lack of Ca(v)2.3 resulted in a marked decrease in the sensitivity of the animal to γ-butyrolactone-induced absence epilepsy. Local blockade of Ca(v)2.3 channels in the RT mimicked the results of Ca(v)2.3⁻/⁻ mice. These results provide strong evidence that Ca(v)2.3 channels are critical for oscillatory burst discharges in RT neurons and for the expression of absence epilepsy.
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 4 (PLC4) 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. PLC4-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 PLC4 induced spontaneous SWDs with simultaneous behavioral arrests and increased the susceptibility to drug-induced SWDs, indicating that the deletion of thalamic PLC4 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 PLC4-deficient mice as a potential animal model for absence seizures.epilepsy ͉ gene knockdown ͉ knockout mice ͉ thalamus A bsence seizures are generalized nonconvulsive seizures characterized by a brief and sudden impairment of consciousness, concomitant with bilaterally synchronized spike-and-wave discharges (SWDs) in the electroencephalogram (EEG) over wide cortical areas (1-4). Abnormal hypersynchronized oscillatory activities in the thalamocortical network, consisting of feedforward and feedback connections between the cortex and the thalamus, have been implicated as an underlying mechanism for the generation of SWDs (5-9). Some studies using rat models of absence seizures have suggested that the cortex plays a leading role in the generation of SWDs (10-13). Other studies support the hypothesis that massive thalamocortical synchronization is driven from recurrent oscillatory activities in the network between reticular thalamic nucleus (nRT) and thalamocortical (TC) relay nucleus (3,8,9,14,15). A majority of these studies proposed a leading role for nRT neurons in the genesis of absence seizures. Relatively less attention has been directed on the role of TC neurons in the generation of SWDs. Thalamocortical network oscillations are often observed to be accompanied by a shift in the firing pattern of thalamocortical (TC) neurons from tonic to burst firing (16). Low-threshold burst firing driven by T-type Ca 2ϩ currents in TC neurons has long been proposed to be a critical component in sustaining the oscillations during the SWDs (3,8,17), although a controversy still remains (4, 18).Many studies have described spontaneous appearance of SWDs in the cortical EEG from rodent models for absence epilepsy (19)(20)(21)(22)(23)(24). Some showed that T-type Ca 2ϩ currents were incre...
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