MGlu7 potentiation rescues cognitive, social, and respiratory phenotypes in a mouse model of Rett syndrome

Rocco G. Gogliotti, Rebecca K. Senter, Nicole M. Fisher, Jeffrey Adams, Rocio Zamorano, Adam G. Walker, Anna L. Blobaum, Darren W. Engers, Corey R. Hopkins, J. Scott Daniels, Carrie K. Jones, Craig W. Lindsley, Zixiu Xiang, P. Jeffrey Conn, Colleen M. Niswender

Research output: Contribution to journalArticle

26 Scopus citations

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.

Original languageEnglish (US)
Article numbereaai7459
JournalScience translational medicine
Volume9
Issue number403
DOIs
StatePublished - Aug 16 2017

ASJC Scopus subject areas

  • Medicine(all)

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    Gogliotti, R. G., Senter, R. K., Fisher, N. M., Adams, J., Zamorano, R., Walker, A. G., Blobaum, A. L., Engers, D. W., Hopkins, C. R., Daniels, J. S., Jones, C. K., Lindsley, C. W., Xiang, Z., Conn, P. J., & Niswender, C. M. (2017). MGlu7 potentiation rescues cognitive, social, and respiratory phenotypes in a mouse model of Rett syndrome. Science translational medicine, 9(403), [eaai7459]. https://doi.org/10.1126/scitranslmed.aai7459