Genetic Reduction or Negative Modulation of mGlu₇ Does Not Impact Anxiety and Fear Learning Phenotypes in a Mouse Model of MECP2 Duplication Syndrome.

Rett syndrome and MECP2 Duplication syndrome are neurodevelopmental disorders attributed to loss-of-function mutations in, or duplication of, the gene encoding methyl-CpG-binding protein 2 (MeCP2), respectively. We recently reported decreased expression and function of the metabotropic glutamate receptor 7 (mGlu₇) in a mouse model of Rett syndrome. Positive allosteric modulation of mGlu₇ activity was sufficient to improve several disease phenotypes including cognition. Here, we tested the hypothesis that mGlu₇ expression would be reciprocally regulated in a mouse model of MECP2 Duplication syndrome, such that negative modulation of mGlu₇ activity would exert therapeutic benefit. To the contrary, we report that mGlu₇ is not functionally increased in mice overexpressing MeCP2 and that neither genetic nor pharmacological reduction of mGlu₇ activity impacts phenotypes that are antiparallel to those observed in Rett syndrome model mice. These data expand our understanding of how mGlu₇ expression and function is affected by changes in MeCP2 dosage and have important implications for the therapeutic development of mGlu₇ modulators.

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