Research ArticleRett Syndrome

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

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Science Translational Medicine  16 Aug 2017:
Vol. 9, Issue 403, eaai7459
DOI: 10.1126/scitranslmed.aai7459

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A positive approach to Rett syndrome

Rett syndrome is an untreatable neurodevelopmental disorder. Gogliotti et al. report a decrease in metabotropic glutamate receptor 7 (mGlu7) expression in brain autopsy samples from patients with Rett syndrome. The authors used in vitro electrophysiological and in vivo pharmacological and behavioral analyses to test whether restoring mGlu7 ameliorated deficits in two Rett syndrome mouse models. mGlu7 reduction disrupted synaptic plasticity in the hippocampus; positive modulation of mGlu7 activity restored synaptic plasticity and reduced cognitive impairments and apneas in the mice. These findings suggest that mGlu7 might be a useful therapeutic target for treating Rett syndrome.

Abstract

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.

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