0071 Determining the Importance of Gap Junction Protein connexin36 in Sleep-wakefulness and Task-evoked EEG Activity
Year: 2025
Type: conference-abstract
Abstract: Introduction Neuronal gap junctions, also termed electrical synapses consisting of connexin36 (Cx36) protein, are extensively expressed in the mammalian forebrain and are suggested to play a significant role in state regulation and thalamocortical network activity. Cx36 is predominantly expressed in GABAergic neurons in the adult brain and represents a common mechanism for electrical coupling between inhibitory neurons. Specifically, the intercellular communications between the GABAergic neurons in the thalamic reticular nucleus (TRN) occur predominantly via Cx36 containing electrical synapses. We have examined the effect of a Cx36 global gene knockout (KO) and TRN-specific localized CRISPR-Cas-mediated Cx36 gene knockdown (KD) on sleep/wake state and spontaneous and evoked EEG activity. Methods We examined the sleep/wake state, spontaneous and task-evoked EEG activity in auditory steady-state response (ASSR), mismatch negativity (MMN), and social interaction behavioral test in Cx36KO mice and in PV-Cre-Cas9 mice before and after localized Cx36 gene KD. Results While Cx36KO mice exhibited limited sleep/wake abnormalities, power spectral density analysis of spontaneous EEG activity revealed significant impairment in gamma and beta band activity. Interestingly, sigma band activity significantly decreased prior to NREM-REM transitions. While we observed no changes in sleep spindle density, the amplitude and duration of spindles showed statistically significant decreases in Cx36KO mice. Additionally, Cx36KO mice exhibited a blunted gamma band response to acute ketamine (15 mg/kg; IP), impaired 40 Hz ASSR, and an abnormal response in the mismatch negativity task (decreased ERP peak amplitude & evoked-power). Finally, Cx36KO mice exhibit significant impairment in social investigation-induced low-frequency gamma band activity. Preliminary observations in TRN-Cx36 KD mice showed similar impairment in ASSR and social investigation-induced gamma band activity. Conclusion Our data suggests that Cx36 is involved in regulating thalamocortical network activity. Further, impairments in Cx36KO mice are consistent with abnormalities observed in neuropsychiatric disorders, including schizophrenia, suggesting Cx36 containing gap junctions as a novel therapeutic target. Support (if any) VA Biomedical Laboratory Research and Development Merit Award I01 BX006105(R.B.); I01 BX004500 (JMM); I01 BX006550 (DSU); IK2 BX004905 (DSU); R01 NS119227 (R.B.).
Source: SLEEP
Authors: Radhika Basheer, Sean Carey, Victoria Lombardi, DAVID uygun, James M McNally
Institutions: Harvard University, VA Boston Healthcare System
Language: English
Topic: Connexins and lens biology
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4410502683