663. REPETITIVE NEURONAL ACTIVATIONS REGULATE CELLULAR MATURATION STATE VIA NUCLEAR REPROGRAMMING

Abstract Background Repetitive neural stimulations, including electroconvulsive therapy (ECT), effectively treat various psychiatric disorders, but the cellular mechanisms underlying these benefits remain unclear. Emerging evidence suggests that repetitive neuronal activation might trigger cellular dematuration, with which mature neurons return to pseudo-immature status, potentially underlying observed therapeutic effects. Aims & Objectives This study aimed to clarify the cellular and molecular events induced by repetitive neuronal activations, specifically investigating how neuronal stimulation promotes cellular dematuration and nuclear reprogramming, contributing to therapeutic outcomes observed clinically. Method We used transgenic mice expressing Channelrhodopsin-2 and applied repetitive optogenetic stimulation (REPOPS) to granule cells in the dentate gyrus, mimicking clinical electroconvulsive therapy (ECT). Cellular dematuration was assessed via RNA sequencing (RNA-seq) for transcriptomic profiling, ATAC sequencing (ATAC-seq) for chromatin accessibility, and nuclear structural analysis (lamin B1 disruption, phosphorylated histone H3, and chromocenter condensation). Additionally, we conducted in vivo Ca2+ imaging to evaluate alterations in neuronal coding of spatial and speed information. The role of cyclin B was investigated through in vivo genome editing with AAV-mediated CRISPR/Cas9 targeting. Results Repeated neuronal activation for ten consecutive days resulted in sustained cellular dematuration in dentate gyrus granule cells, demonstrated by significant nuclear reprogramming, chromatin remodeling, and long-lasting nuclear structural changes. Transcriptomic and chromatin analyses revealed persistent alterations involving cell cycle-related genes, particularly cyclin B. Ca2+ imaging indicated long-term impairments in spatial coding and enhancements in speed information coding by dentate gyrus neurons. Cyclin B knockout effectively reduced stimulation-induced nuclear structural and behavioral alterations, confirming its essential regulatory function. Discussion & Conclusions Our findings identify a novel mechanism of action for repetitive brain stimulation therapies such as ECT, involving nuclear reprogramming and neuronal re-entry into a G2/M-phase-like immature state. This immature state acts as a therapeutic intermediate, facilitating beneficial clinical outcomes, including anti-depressive effects and increased activity, though accompanied by memory encoding impairments. This study provides new insights into activity-dependent cellular plasticity relevant to neuropsychiatric treatments.