Insights on the role of external globus pallidus in controlling absence seizures

Abstract Absence epilepsy, characterized by transient loss of awareness and bilaterally synchronous 2-4 Hz spike and wave discharges (SWDs) on electroencephalography (EEG) during absence seizures, is generally believed to arise from abnormal interactions between the cerebral cortex (Ctx) and thalamus. Recent animal electrophysiological studies suggested that changing the neural activation level of the external globus pallidus (GPe) neurons can remarkably modify firing rates of the thalamic reticular nucleus (TRN) neurons through the GABAergic GPe-TRN pathway. However, the existing experimental evidence does not provide a clear answer as to whether the GPe-TRN pathway contributes to regulating absence seizures. Here, using a biophysically based mean-field model of the GPe-corticothalamic (GCT) network, we found that both directly decreasing the strength of the GPe-TRN pathway and inactivating GPe neurons can effectively suppress absence seizures. Also, the pallido-cortical pathway and the recurrent connection of GPe neurons facilitate the regulation of absence seizures through the GPe-TRN pathway. Specifically, in the controllable situation, enhancing the coupling strength of either of the two pathways can successfully terminate absence seizures. Moreover, the competition between the GPe-TRN and pallido-cortical pathways may lead to the GPe bidirectionally controlling absence seizures, and this bidirectional control manner can be significantly modulated by the Ctx-TRN pathway. Importantly, when the strength of the Ctx-TRN pathway is relatively strong, the bidirectional control of absence seizures by changing GPe neural activatives can be observed at both weak and strong strengths of the pallido-cortical pathway.These findings suggest that the GPe-TRN pathway may have crucial functional roles in regulating absence seizures, which may provide a testable hypothesis for further experimental studies and new perspectives on the treatment of absence epilepsy.