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Daisuke KASE"The role of the basal ganglia in absence seizure"

Abstract :

Absence seizures consist of a brief and sudden impairment of consciousness.
They are characterized by bilaterally synchronized spike and wave discharges (SWDs), which reflect abnormal oscillations in the thalamocortical loop. Recent studies have suggested that the basal ganglia are involved in generation of the SWDs, but their roles are poorly understood at the molecular and cellular levels. Here, we studied the pathophysiological roles of the basal ganglia using in vivo and in vitro measurements of tottering mice, a well-established model of absence epilepsy. We found that the membrane excitability of the subthalamic nucleus (STN) neurons was enhanced in tottering mice, which resulted from reduced hyperpolarization-activated cyclic nucleotide-gated (HCN) channel activity. Pharmacological blockade and activation of HCN channel activity in vitro bidirectionally altered the membrane excitability of the STN neurons. Furthermore, these pharmacological modulations of HCN channel activity in the STN in vivo bidirectionally altered the mean SWD duration. In addition, STN deep brain stimulation modulated SWDs in a frequency-dependent manner. These results indicate that STN is involved in the rhythm maintenance system of absence seizures. In order to uncover the mechanism underlying rhythm maintenance system, we focused on inhibitory projection from the substantia nigra pars reticulata (SNr) to the ventral medial (VM) nucleus of the thalamus. Since the mechanism of information transfer via this inhibitory synapses remains unclear, we recorded and analyzed the synaptic transmission by using slice preparations of wild-type mice. To discriminate the synaptic transmission from SNr to VM, we developed a special slice preparation that contains projection fibers from SNr to the VM nucleus. Using this preparation, we succeeded to record nigral IPSCs from VM neurons, and constructed a model circuit between SNr and VM using the obtained experimental data. Simulation of nigro-thalamic circuit implies that the synchronous inhibitory inputs can evoke synchronous activities in the VM nucleus. With these results, inhibitory projection from SNr to VM may enhance the rhythmic activity of absence seizure in the VM nucleus.

Selected publications

Roles of the subthalamic nucleus and subthalamic HCN channels in absence seizures.Kase D, Inoue T, Imoto K.J Neurophysiol. 2012 Jan;107(1):393-406. Epub 2011 Oct 19.

Thomas Boraud de l'IMN