Hypnotic treatment improves sleep architecture and EEG disruptions and rescues memory deficits in a mouse model of fragile X syndrome

Fragile X syndrome (FXS) is associated with disrupted cognition and sleep abnormalities. Sleep loss negatively impacts cognitive function, and one untested possibility is that disrupted cognition in FXS is exacerbated by abnormal sleep. We tested whether ML297, a hypnotic acting on G-protein-activated inward-rectifying potassium (GIRK) channels, could reverse sleep phenotypes and disrupted memory in Fmr1−/y mice. Fmr1−/y mice exhibit reduced non-rapid eye movement (NREM) sleep and fragmented NREM architecture, altered sleep electroencephalogram (EEG) oscillations, and reduced EEG coherence between cortical areas; these are partially reversed following ML297 administration. Treatment following contextual fear or spatial learning restores disrupted memory consolidation in Fmr1−/y mice. During memory recall, Fmr1−/y mice show an altered balance of activity among hippocampal principal neurons vs. parvalbumin-expressing interneurons; this is partially reversed by ML297. Because sleep disruption could impact neurophysiological phenotypes in FXS, augmenting sleep may improve disrupted cognition in this disorder.