Metabotropic glutamate receptor 7 as a potential genetic modifier of cognitive deficits in neurofibromatosis

Vanderbilt University, Nashville TN

Investigators

Abstract

PROJECT SUMMARY Neurofibromatosis Type 1 (NF1) is an autosomal dominant disorder characterized by the growth of nerve tumors, skin pigmentation abnormalities, and optic gliomas. NF1 is caused by mutations in neurofibromin (NF), a protein that increases the hydrolysis of Ras-bound GTP, resulting in Ras inactivation. Loss of NF leads to unchecked cellular growth, resulting in the neurofibromas characteristic of the disease. In addition to these symptoms, up to 75% NF1 patients present with learning disabilities, including dyslexia and spatial learning challenges, and almost 40% of children with NF1 have attention deficit hyperactivity disorder (ADHD). The incomplete penetrance of the learning disabilities suggests that there may be modifier genes that enhance the susceptibility of an NF1 patient to learning difficulties. Metabotropic glutamate receptor 7 (mGlu7, GRM7) is a group III metabotropic glutamate (mGlu) receptor that regulates presynaptic neurotransmitter release. Primary mutations in GRM7 cause severe neurodevelopmental phenotypes including seizures, ADHD, and intellectual impairments. The receptor is required for the induction of long-term potentiation (LTP) in the hippocampus by reducing GABA release, and Grm7-/- animals show deficits in learning and memory paradigms and a blunted response to amphetamine. A PheWAS study performed using the Vanderbilt BioVU database identified a correlation between a GRM7 SNP (rs9870680) with NF1, and we have found that this SNP also correlates with mGlu7 protein expression in the human brain. Mice modeling NF1 exhibit deficits in hippocampal LTP and behavioral abnormalities in learning and memory paradigms caused by excessive presynaptic GABA release; we hypothesize that increasing mGlu7 activity will reverse this effect. In support of this hypothesis, a single dose of a positive allosteric modulator (PAM) with activity at mGlu7, VU0422288, corrects a contextual fear learning deficit in an Nf1 mutant mouse line that exhibits learning impairments in multiple cognition models. In NF1 patients, the rate of learning deficits and ADHD is significantly higher than the general population; however, there is incomplete penetrance of these phenotypes, suggesting a possible modifier role for other genes when a patient also has NF1. PheWAS analysis has linked GRM7 gene with neurofibromatosis, and primary mutations in GRM7 cause ADHD and learning impairments. Coupled with the observations that genetic status at one of the identified SNPs correlates with mGlu7 protein expression and the finding that mGlu7 potentiation corrects impairments in Nf1 mutant mice in a learning model, our overall hypothesis is that mGlu7 potentiation represents a novel therapeutic strategy to address learning challenges in NF1. The goal of this R21 application is to test the hypothesis that the interaction of mGlu7 and neurofibromin lies at the level of GABA release and to validate that mGlu7 may represent a novel drug target for learning deficits in NF1.