An acetylcholine-inhibited sleep-active hippocampal interneuron orchestrates memory consolidation

Memory reactivation during hippocampal ripples is critical for sleep-dependent memory consolidation. However, the molecular-to-circuit mechanism enabling sleep-predominant ripple generation remains unresolved. Here, we discovered that a sparse population of GABAergic interneurons in the mouse hippocampus specializes in gating ripple generation and memory consolidation. While all known genetically labeled hippocampal interneurons were highly active during wakefulness and rapid-eye-movement (REM) sleep, genetic targeting of M2 acetylcholine receptor (Chrm2)-expressing neurons isolated a specific population preferentially active during non-REM (NREM) sleep and quiet wakefulness. These acetylcholine-inhibited interneurons inhibited the entire hippocampus in an infra-slow rhythm (∼0.015 Hz). Suppressing their activity in dorsal CA3 or ventral hippocampus impaired spatial and social memory, respectively. Furthermore, Chrm2+ neurons were closely associated with ripples; their activity bidirectionally modulated ripple occurrence via widespread inhibition. Thus, Chrm2+ interneurons are critical in linking neuromodulatory state to memory consolidation, offering genetically targeted access to sleep-active memory circuits implicated in cognitive disorders.