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

Fisher NM, Gogliotti RG, Vermudez SAD, Stansley BJ, Conn PJ, Niswender CM
ACS Chem Neurosci. 2018 9 (9): 2210-2217

PMID: 29227625 · PMCID: PMC6002927 · DOI:10.1021/acschemneuro.7b00414

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 (mGlu) in a mouse model of Rett syndrome. Positive allosteric modulation of mGlu activity was sufficient to improve several disease phenotypes including cognition. Here, we tested the hypothesis that mGlu expression would be reciprocally regulated in a mouse model of MECP2 Duplication syndrome, such that negative modulation of mGlu activity would exert therapeutic benefit. To the contrary, we report that mGlu is not functionally increased in mice overexpressing MeCP2 and that neither genetic nor pharmacological reduction of mGlu activity impacts phenotypes that are antiparallel to those observed in Rett syndrome model mice. These data expand our understanding of how mGlu expression and function is affected by changes in MeCP2 dosage and have important implications for the therapeutic development of mGlu modulators.

MeSH Terms (13)

Allosteric Regulation Animals Anxiety Benzoxazoles Disease Models, Animal Excitatory Amino Acid Agonists Fear Learning Mental Retardation, X-Linked Mice Phenotype Phosphinic Acids Receptors, Metabotropic Glutamate

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