Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the () gene. The cognitive impairments seen in mouse models of RTT correlate with deficits in long-term potentiation (LTP) at Schaffer collateral (SC)-CA1 synapses in the hippocampus. Metabotropic glutamate receptor 7 (mGlu) is the predominant mGlu receptor expressed presynaptically at SC-CA1 synapses in adult mice, and its activation on GABAergic interneurons is necessary for induction of LTP. We demonstrate that pathogenic mutations in reduce mGlu protein expression in brain tissue from RTT patients and in MECP2-deficient mouse models. In rodents, this reduction impairs mGlu-mediated control of synaptic transmission. We show that positive allosteric modulation of mGlu activity restores LTP and improves contextual fear learning, novel object recognition, and social memory. Furthermore, mGlu positive allosteric modulation decreases apneas in mice, suggesting that mGlu may be a potential therapeutic target for multiple aspects of the RTT phenotype.
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