Overexpression of mGlu(7B) in Mice: Implications for Neurodevelopmental Disorders.

Metabotropic glutamate receptor 7 (mGlu(7)) is a G protein-coupled receptor (GPCR) involved in neurotransmitter release throughout the central nervous system (CNS). Low levels of the receptor are correlated with intellectual disability, autism, repetitive behaviors, and seizures in patients with neurodevelopmental disorders (NDDs), including the disease Rett syndrome. These findings suggest that increasing mGlu(7) activity may be of therapeutic benefit. In the current manuscript, we report the characterization of a novel transgenic mouse that overexpresses the human GRM7B splice variant at approximately fivefold higher levels compared to wild-type (WT) littermates. These animals exhibit a reciprocal decrease in expression of the mouse mGlu(7A) splice isoform, suggesting feedback regulation of receptor expression. Previous studies from our lab and others have shown that mGlu(7) activation is permissive for long-term potentiation induction in the hippocampus and amygdala. Here, we identified subtle differences in agonist-modulated hippocampal field recordings in mice overexpressing mGlu(7B), but no changes in theta burst-induced long-term potentiation. Our lab previously characterized behavioral phenotypes in Grm7(-/-) animals that were observed in other animal models of NDDs. Surprisingly, we find here that mGlu(7B)-overexpressing mice exhibit similar phenotypes to previously reported studies in Grm7(-/-) animals in repetitive behavior and cognition assays. Overall, these findings suggest that precise control of mGlu(7) may be required to avoid abnormal phenotypes.