Cortical GABAergic dynamics around hippocampal sharp-wave ripples

Abstract

Hippocampal sharp-wave ripples (SWRs) coordinate hippocampal-neocortical interactions for memory consolidation, yet how cortical GABA signaling is organized around SWRs remains unclear. Here we approach this problem by combining wide-field mesoscale imaging of extracellular GABA using iGABASnFR2 with simultaneous dorsal CA1 electrophysiology and sleep-state monitoring in mice, enabling GABA dynamics to be mapped across 17 cortical regions during natural sleep and wakefulness. Using ripple-triggered activity mapping and singular value decomposition, we identified a cortex-wide GABA response consisting of a dominant global component and regionally structured components that were reconfigured across brain states. Across cortical subnetworks, SWRs were associated with a reduction in GABA signaling followed by widespread activation, with both components enhanced during NREM sleep. During NREM sleep, GABA responses emerged earliest and most strongly in the retrosplenial and other medial cortical regions before progressing laterally. During wakefulness, responses were faster, preferentially recruited lateral sensory regions and progressed towards medial cortex. Transitions between NREM sleep, REM sleep and wakefulness were also accompanied by distinct changes in GABA signaling and interregional network organization. Our findings suggest a model in which hippocampal SWRs recruit a shared cortex-wide GABA response whose regional expression and direction of propagation are reconfigured by brain state, providing a dynamic inhibitory framework for regulating hippocampal-neocortical communication.