mGlu₇ potentiation rescues cognitive, social, and respiratory phenotypes in a mouse model of Rett syndrome

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the methyl-CpG binding protein 2 (MECP2) 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 (mGlu₇) 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 MECP2 reduce mGlu₇ protein expression in brain tissue from RTT patients and in MECP2-deficient mouse models. In rodents, this reduction impairs mGlu₇-mediated control of synaptic transmission. We show that positive allosteric modulation of mGlu₇ activity restores LTP and improves contextual fear learning, novel object recognition, and social memory. Furthermore, mGlu₇ positive allosteric modulation decreases apneas in Mecp2 mice, suggesting that mGlu₇ may be a potential therapeutic target for multiple aspects of the RTT phenotype.