Metabotropic Glutamate Receptor 7 as a Novel Therapeutic Target for MECP2 Duplication Syndrome

Vanderbilt University, Nashville TN

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Abstract

PROJECT SUMMARY Loss-of-function mutation of the Methyl CpG Binding Protein 2 (MECP2) gene causes a severe neurodevelopmental disorder known as Rett syndrome (RTT), while duplication of its locus leads to MECP2 Duplication syndrome (MDS). Children with each diagnosis can present with profound intellectual disability for which there is currently no treatment. Here we provide preliminary data showing that expression of the metabotropic glutamate receptor 7 (mGlu7), a receptor with known roles in synaptic plasticity and cognition, is altered downstream of changes in MECP2 gene dosage. While potentiation of mGlu7 activity ameliorates phenotypes in RTT mice, the therapeutic potential of mGlu7 modulation in a model of MDS remains unexplored. Completion of this research proposal will thoroughly investigate the efficacy of mGlu7 modulation in paradigms of learning and memory in a mouse model of MDS and provide new mechanistic insight into the neurophysiological role of mGlu7 in the context of MeCP2-related disorders.