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

Sci Transl Med. 2017 Aug 16;9(403):eaai7459. doi: 10.1126/scitranslmed.aai7459.


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.

MeSH terms

  • Animals
  • Apnea / drug therapy
  • Apnea / physiopathology
  • Autopsy
  • CA1 Region, Hippocampal / drug effects
  • CA1 Region, Hippocampal / metabolism
  • Cognition*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Long-Term Potentiation / drug effects
  • Male
  • Memory / drug effects
  • Methyl-CpG-Binding Protein 2 / deficiency
  • Methyl-CpG-Binding Protein 2 / metabolism
  • Mice
  • Motor Cortex / drug effects
  • Motor Cortex / metabolism
  • Motor Cortex / pathology
  • Neuronal Plasticity / drug effects
  • Phenotype
  • Picolinic Acids
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats, Sprague-Dawley
  • Receptors, Metabotropic Glutamate / genetics
  • Receptors, Metabotropic Glutamate / metabolism*
  • Respiration* / drug effects
  • Rett Syndrome / metabolism*
  • Rett Syndrome / pathology
  • Rett Syndrome / physiopathology*
  • Social Behavior*
  • Transcription, Genetic / drug effects


  • Methyl-CpG-Binding Protein 2
  • Picolinic Acids
  • RNA, Messenger
  • Receptors, Metabotropic Glutamate
  • VU0422288
  • metabotropic glutamate receptor 7