Metabotropic Glutamate Receptor 7: Implications for the Etiology and Treatment of Neurodevelopmental Disorders

Abstract

The metabotropic glutamate receptor 7 (mGlu7) is a G protein-coupled receptor that plays important roles in synaptic transmission and plasticity in the brain. mGlu7 is expressed presynaptically on excitatory and inhibitory neurons, and its activation inhibits the release of glutamate and GABA, respectively. Previous work has shown that mGlu7 protein expression is decreased in Rett syndrome, a rare monogenic neurodevelopmental disorder (NDD), and that potentiation of mGlu7 activity improves hippocampal long-term potentiation and associated learning deficits in a Rett syndrome mouse model. In Chapter II of this dissertation we evaluate mGlu7 as a therapeutic target for a related disorder, MECP2 Duplication syndrome. Despite having opposing phenotypes to Rett syndrome model mice, the behavior of MECP2 Duplication syndrome model mice was not impacted by genetic reduction of mGlu7 expression or pharmacological inhibition of mGlu7 activity. Variants in the GRM7 gene have been identified in patients with other NDDs such as autism and intellectual disability, indicating that mGlu7 may play a broad role in NDD-associated behaviors. To test this hypothesis, we characterized a global mGlu7 knockout mouse line in Chapter III. We report novel alterations in social behavior, movement, sleep and sensitivity to amphetamine in addition to replicating previously observed learning deficits and seizures. Many of these phenotypes overlap with those observed in Rett syndrome patients, further validating mGlu7 as therapeutic target for this indication. Finally, in Chapter IV we report two patients with global developmental delay and epilepsy who carry a homozygous point mutation in the mGlu7 ligand-binding domain. We show that this mutation weakens receptor dimerization and prevents proper trafficking and expression. In a point mutant mouse model, mGlu7 protein was virtually absent and these mice recapitulated symptoms seen in the patients including learning deficits, decreased motor coordination and seizures. In summary, this work confirms that GRM7 can be a disease-causing gene in humans and suggests that reductions in mGlu7 expression or function may contribute to NDDs.