0094 The Role of the Thalamic Reticular Nucleus Connexin36 in Sleep-Wakefulness and Task-Evoked EEG Activity

Introduction Neuronal gap junction protein connexin36 (Cx36) forms electrical synapses. They are widely expressed in the mammalian forebrain and are suggested to play a significant role in state regulation and thalamocortical network activity. Cx36 is expressed in GABAergic neurons in the adult brain and is responsible for the electrical coupling between inhibitory neurons. Specifically, the intercellular communications between GABAergic neurons in the thalamic reticular nucleus (TRN) occur predominantly via Cx36-containing electrical synapses. We have examined the effect of TRN-specific localized CRISPR-Cas-mediated Cx36 gene knockdown (KD) on sleep/wake, spontaneous, and evoked EEG activity. Methods We examined the sleep/wake pattern, spontaneous and task-evoked EEG activity during auditory steady-state response (ASSR), and social interaction behavioral test in PV-Cre-Cas9 mice before and after TRN-PV neuron-selective Cx36 gene KD. Results Cx36KO mice exhibited limited sleep/wake abnormalities. Cx36KD mice exhibited an impaired 40 Hz ASSR, and significant impairment in social investigation-induced low-frequency gamma band activity. Preliminary results from localized CRISPR KD of TRN-Cx36 KD (N=5 mice) showed a trending 30.67% reduction in evoked cortical gamma power during ASSR when compared to the pre-AAV-injection condition in the same mice. Preliminary observations (N=2 mice) in our social investigation task the gamma power showed a trending attenuation (-9.21%), in post-injection Cx36KD condition compared to baseline, suggesting a modulatory effect of TRN Cx36 KD on task-evoked cortical gamma activity. Conclusion Our data suggest that Cx36 in TRN is involved in regulating oscillatory activity in the thalamocortical network. These observations are the first to suggest that TRN Cx36 KD causes impairments in task-evoked cortical gamma activity that are consistent with abnormalities observed in neuropsychiatric disorders, including schizophrenia, suggesting Cx36 as a novel therapeutic target. Support (if any) VA Merit Award I01 BX006105(R.B.); I01 BX004500 (J.M.M.); IK2 BX004905 (D.S.U.); R01 NS119227 (R.B.).