Deletion of phospholipase C β4 in thalamocortical relay nucleus leads to absence seizures

Abstract

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 (PLC␤4) 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. PLC␤4-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 PLC␤4 induced spontaneous SWDs with simultaneous behavioral arrests and increased the susceptibility to drug-induced SWDs, indicating that the deletion of thalamic PLC␤4 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 PLC␤4-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...

Sleep spindles are generated in the absence of T-type calcium channel-mediated low-threshold burst firing of thalamocortical neurons

“…Taken together, these findings suggest that spindle oscillations can be generated and propagated via any type of TC spike activity as long as TC neurons discharge spikes at an appropriate frequency. This conclusion differs from previous observations on the critical role of TC T-type channels in sleep delta waves (16) and paroxysmal SWDs (13,32,33), and leads us to suggest that the various TC oscillations may be generated through diverse mechanisms. Ca V 3.1 T-Type Channels in Spindles vs. SWDs.…”

“…Previous studies have found that Ca V 3.1 −/− mice are resistant to GABA B receptor agonist-induced SWDs (13), and that deletion of Ca V 3.1 completely suppresses or markedly reduces SWDs in genetic mouse models of absence seizures (35), implying that Ca V 3.1 T-type Ca 2+ channels play a crucial role in the genesis of SWDs. In contrast, the increased T-type Ca 2+ currents in TC neurons occur alongside the generation of SWDs and absence seizure phenotypes in transgenic or mutant mice (32,33). Our present findings support the hypothesis that Ca V 3.1 Ttype Ca 2+ channels are not an essential component in the generation of sleep spindles.…”

The thalamic mGluR1-PLCβ4 pathway is critical in sleep architecture

“…The PLCβ4 −/− mice exhibited mild absence seizures, as has been previously reported [26], with occasional spike-wave discharges (SWDs) in the EEG recordings (green vertical bars in the extended hypnogram plot in the upper panel in Fig. 1d).…”

High Resolution Electroencephalography in Freely Moving Mice

“…This result is in line with previous finding with a rat model with spontaneous absence seizure showing that SWDs are initiated in the facial region of the somatosensory cortex (Meeren et al 2002). Recently genetic studies have contributed to the understanding of generation of absence seizure in the molecular level, for instance, the ␣1G subunit of low-voltageactivated T-type Ca 2ϩ channels in thalamocortical relay neurons are involved in the genesis of absence seizure (Kim et al 2001); on the other hand, phospholipase C ␤4 in the thalamic reticular neuron conduces absence seizure (Cheong et al 2009). However, it is true that these genes have a role as modulator rather than exterminator or source for SWDs.…”