Phenotypic profiling of mGlu overexpressing mice and its implications for neurodevelopmental disorders such as Rett syndrome. Journal Article

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Authors: Buch, A; Fisher, N; Frietas, G; Vermudez, S; Weiss, K; Gogliotti, R; Niswender, C
Article Title: Phenotypic profiling of mGlu overexpressing mice and its implications for neurodevelopmental disorders such as Rett syndrome.
Abstract: Neurodevelopmental disorders (NDDs) are characterized by deficits in communication, cognition, attention, social behavior and/or motor control. Previous studies have pointed to the involvement of genes that regulate synaptic structure and function in the pathogenesis of these disorders. One such gene, GRM7, encodes the metabotropic glutamate receptor 7 (mGlu ), a G protein-coupled receptor that regulates presynaptic neurotransmitter release. Mutations and polymorphisms in GRM7 have been associated with (NDDs) in clinical populations; however, limited preclinical studies have evaluated mGlu in the context of this specific disease class. Rett syndrome (RTT) is an NDD caused by mutations in the Methyl-CpG Binding Protein 2 (MECP2) gene. The cognitive deficits seen in RTT model mice have been previously correlated with a deficit in long-term potentiation (LTP) at Schaffer collateral-CA1 (SC-CA1) synapses in the hippocampus. mGlu is abundantly expressed presynaptically at SC-CA1 synapses and its role in the regulation of GABA release is imperative for the induction of LTP. Previous studies from our lab have shown that mGlu expression is reduced in autopsy samples from patients diagnosed with RTT and in mouse models of RTT. Our lab has also shown that abnormal phenotypes in RTT mice can be corrected with mGlu positive allosteric modulators (PAMs). Despite the beneficial effects of mGlu potentiation, it is important to understand how an increase in mGlu expression affects phenotypes seen in NDDs like Rett syndrome. Here, we hypothesize that an excess of either of the two mGlu isoforms, mGlu a and mGlu b, in mice is sufficient to alter phenotypes. mGlu was globally overexpressed in mice by crossing a Grm7(a/b) male with a CMV-Cre female. Starting at 6 weeks of age, behavioral assays were conducted for motor, cognitive, and stereotypic phenotypes. After the behavioral phenotyping, tissue was collected and processed for expression studies. Our data indicate abnormal phenotypes in motor, cognitive, and stereotypic assays. In particular, mGlu over-expressing mice, regardless of isoform, display hyperactivity in a locomotor assay, associative memory deficits in a contextual fear conditioning assay, and increased repetitive behaviors as assessed by hindlimb clasping. In conclusion, our study indicates that overexpressing mGlu in mice leads to abnormal phenotypes. We are now assessing synaptic plasticity phenotypes, including abnormal long-term potentiation in mGlu overexpressing mice, and determining the effect of mGlu allosteric modulators in affecting these cognitive aberrations. Overall, these studies aim to capitalize on previous studies demonstrating the role of mGlu in the manifestation of phenotypes associated with NDDs.
Journal Title: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860; 0892-6638
Publisher: Unknown  
Date Published: 2022