REM sleep reduces subthreshold depolarization in cortical pyramidal neurons in a region-specific manner

Distinct cell-type- and region-specific patterns modulate cortical microcircuit activity across sleep-wake states. Here, we characterized the subthreshold membrane potentials of pyramidal (PYR) neurons during wakefulness, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep using in vivo whole-cell patch-clamp recordings in head-restrained mice. We found that L2/3 PYR neurons in the prefrontal cortex exhibited a reduction of subthreshold membrane depolarization during REM sleep. In contrast, PYR neurons in the retrosplenial cortex (RSC) displayed an increase in membrane depolarization, suggesting regional differences in cortical excitability. The pharmacological blockade of N-methyl-D-aspartate receptors (NMDARs) selectively decreases subthreshold depolarization during REM sleep, underscoring a role for NMDAR-mediated currents in this state. We showed that the sleep-promoting drug diazepam reduced membrane depolarization of PYR neurons in the prefrontal cortex, possibly due to a disinhibition of parvalbumin interneurons. These findings demonstrate that the modulation of membrane potential of cortical PYR neurons across sleep-wake states relies on distinct excitatory and inhibitory synaptic mechanisms operating in a region-specific manner.