Title: Roles of the Subthalamic Nucleus and Subthalamic Hcn Channels in 1 Absence Seizures 2 3 Authors 4

21 Absence seizures consist of a brief and sudden impairment of consciousness. 22 They are characterized by bilaterally synchronized spike and wave discharges 23 (SWDs), which reflect abnormal oscillations in the thalamocortical loops. Recent 24 studies have suggested that the basal ganglia are involved in generation of the 25 SWDs, but their roles are poorly understood at the molecular and cellular levels. 26 Here, we studied the pathophysiological roles of the basal ganglia using in vivo 27 and in vitro measurements of tottering mice, a well-established model of 28 absence epilepsy. We found that the membrane excitability in the subthalamic 29 nucleus (STN) neurons was enhanced in tottering mice, which resulted from 30 reduced hyperpolarization-activated cyclic nucleotide-gated (HCN) channel 31 activity. Pharmacological blockade and activation of HCN channel activity in 32 vitro bidirectionally altered the membrane excitability of the STN neurons. 33 Furthermore, these pharmacological modulations of HCN channel activity in the 34 STN in vivo bidirectionally altered the mean SWD duration. In addition, STN 35 deep brain stimulation modulated SWDs in a frequency-dependent manner. 36