0007 Astrocyte BMAL1 Mediates Circadian Rhythms in Perinenuronal Net Remodeling and Impacts Hippocampal Synaptic Plasticity and Learning Behavior

Abstract Introduction The circadian clock controls a vast array of cellular and organismal functions, from the molecular scale to behavior. But while each cell is regimented by a cell-autonomous clock, few studies in the brain have dissected the circuit and behavioral contributions of cell-specific clocks in astrocytes. Astrocytes are now known to play key roles in regulating synaptic function, circuit activity and behavior, but whether these functions are guided by astrocyte-autonomous clocks is unknown. Here, we report that the core circadian clock in astrocytes controls synaptic strength and plasticity, perineuronal net structure and learning and memory. Methods We employed Cre- inducible deletion of the critical circadian clock gene Bmal1 in astrocytes (Aldh1l1-CreERT2;Bmal1f/f), which abrogates core clock function in a cell type specific manner. We observed variations in hippocampal PNN abundance. On an electrophysiologic level, we also examined synaptic strength and long term potentiation (LTP). On a behavioral level, we examined learning and memory performance in novel object recognition tasks. Results The inducible deletion of the critical circadian clock gene Bmal1 in astrocytes upregulated genes related to extracellular matrix (ECM) remodeling. Consistently, we observed circadian variations in hippocampal PNN abundance in control mice which were abolished in astrocyte-specific Bmal1 knockouts. In line with evidence implicating perineuronal nets (PNNs), and the ECM in general, in synaptic function and plasticity, we found that astrocyte-specific Bmal1 KO mice had increased synaptic strength but blunted long term potentiation (LTP) as well as impaired learning and memory performance in the novel object recognition tasks. Conclusion Taken together, these findings suggest that the astrocyte clock regulates circadian rhythms in perineuronal net abundance as well as synaptic and behavioral learning and memory. Support (if any) This research was supported by an NIH Washington University Department of Anesthesiology Training Grant T32GM108539 and NIH Grant R01AG063743 (to ESM)