Chemical Modulation of Mutant mGlu1 Receptors Derived from Deleterious GRM1 Mutations Found in Schizophrenics

Schizophrenia is a complex and highly heterogeneous psychiatric disorder whose precise etiology remains elusive. While genome-wide association studies (GWAS) have identified risk genes, they have failed to determine if rare coding single nucleotide polymorphisms (nsSNPs) contribute in schizophrenia. Recently, two independent studies identified 12 rare, deleterious nsSNPS in the GRM1 gene, which encodes the metabotropic glutamate receptor subtype 1 (mGlu(1)), in schizophrenic patients. Here, we generated stable cell lines expressing the mGlu(1) mutant receptors and assessed their pharmacology. Using both the endogenous agonist glutamate and the synthetic agonist DHPG, we found that several of the mutant mGlu(1) receptors displayed a loss of function that was not due to a loss in plasma membrane expression. Due to a lack of mGlu(1) positive allosteric modulators (PAM) tool compounds active at human mGlu(1), we optimized a known mGlu4 PAM/mGlu(1) NAM chemotype into a series of potent and selective mGlu(1) PAMs by virtue of a double molecular switch. Employing mGlu(1) PAMs from multiple chemotypes, we demonstrate that the mutant receptors can be potentiated by small molecules and in some cases efficacy restored to that comparable to wild type mGlu(1) receptors, suggesting deficits in patients with schizophrenia due to these mutations may be amenable to intervention with an mGlu(1) PAM. However, in wild type animals, mGlu(1) negative allosteric modulators (NAMs) are efficacious in classic models predictive of antipsychotic activity, whereas we show that mGlu(1) PAMs have no effect to slight potentiation in these models. These data further highlight the heterogeneity of schizophrenia and the critical role of patient selection strategies in psychiatric clinical trials to match genotype with therapeutic mechanism.