The therapeutic potential of mGlu3 modulation in MeCP2-related disorders

Vanderbilt University, Nashville TN

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Abstract

Project Summary Precise levels of the gene regulator Methyl CpG Binding Protein 2 (MeCP2) are known to be a key determinant for proper neurological development and function. The importance of balanced levels of MeCP2 is highlighted by the fact that a loss of MECP2 results in an Autism Spectrum Disorder known as Rett Syndrome; in contrast, duplication of MECP2 leads to a disorder known as MECP2 Duplication syndrome. While Rett Syndrome is an extensively well studied disease area, the molecular etiology of MECP2 Duplication Syndrome remains far less understood. This genetic neurodevelopmental disorder has a wide symptomology including stereotypy, hypotonia, severe cognitive impairments, seizures, and autism. Importantly, both of these disorders critically lack effective therapeutic treatment. Therefore, this research proposal has been designed to develop the candidate?s technical research skills that are necessary to conduct independent neuropharmacology research, while having a positive impact on the field of glutamate systems biology and neurological disorders. In rodent models of MECP2 Duplication Syndrome in which MeCP2 is overexpressed, increases in glutamatergic synapse formation in hippocampal neurons occur, as well as impairments in hippocampal synaptic plasticity and cognitive functions in mice. Interestingly, the metabotropic glutamate receptor 3 (mGlu3) has been shown to be involved in regulating synaptic plasticity and cognitive behaviors in mice, and furthermore, mGlu3 expression has been shown to correlate with MeCP2 expression levels in the brain. Therefore, an upregulation of mGlu3 may contribute to neurological impairments seen in MECP2 Duplication rodent models as well as patients. In support of this theory, we present preliminary data indicating significant increases in mGlu3 protein expression in the hippocampus of mice overexpressing MeCP2 as well as impairment in a form of synaptic plasticity known as long-term depression. It is hypothesized that MeCP2-overexpression causes increases in mGlu3 expression and function, which contribute to synaptic plasticity impairments and cognitive deficits observed in learning and memory paradigms. This will be directly tested by measuring mGlu3-induced second messenger signaling as well as mGlu3-mediated synaptic plasticity and cognitive phenotypes in an animal model of MECP2 Duplication syndrome. Taken together, these studies will elucidate new basic biology and physiology of mGlu3, while also identifying the therapeutic potential of mGlu3 modulation for MeCP2-related disorders.