Development of mGlu7 receptor allosteric modulators for neurological and psychiatric disorders

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PROJECT SUMMARY Metabotropic glutamate receptor 7 (mGlu7) regulates presynaptic neurotransmitter release widely throughout the CNS and is required for the induction of long-term potentiation (LTP) in the hippocampus and amygdala, suggesting a central role in synaptic plasticity. Recently, primary mutations in the GRM7 gene have been linked to intellectual disability, stereotypies, and seizures, symptoms common in neurodevelopmental disorders. Additionally, we have found that mGlu7 protein levels are significantly reduced in the brains of patients clinically diagnosed with the neurodevelopmental disorder, Rett syndrome (RTT). Loss-of-function mutations in Methyl CpG Binding Protein 2 (MECP2), an epigenetic regulation of transcription, are the major cause of RTT, which is a disease resulting in the development of stereotyped behaviors, motor delays, anxiety, cognitive deficits, autistic features, seizures, and apneas. Consistent with reductions in mGlu7 in RTT patients and model mice, potentiating mGlu7 activity with small molecule positive allosteric modulators (PAMs) corrects multiple synaptic plasticity, cognitive, social, and respiratory phenotypes in mice with an Mecp2 knockout (KO) allele. These early studies employed a compound that was not selective for mGlu7 versus several other metabotropic glutamate receptors. We have recently optimized VU6027459, a highly selectivity mGlu7 tool that exhibits suitable pharmacokinetic parameters for in vivo rodent use. Using VU6027459, we have further validated a role for mGlu7 potentiation in reversing abnormal RTT phenotypes. We propose to use the monogenetic disorder of RTT, in tandem with a drug development campaign, as a clinical entry path for the development of mGlu7 PAMs; it is anticipated that future studies could then expand into alternate indications, such as primary epilepsies or schizophrenia. Our previous RTT studies have focused on patients and mice with an MECP2/Mecp2 allele that is a functional null. A large proportion of RTT patients, however, have single point mutations in the MECP2 gene, and our preliminary data suggest that there are differences in mGlu7 expression levels in human RTT tissue that correlate with specific mutations. This indicates that therapeutics for efficacy testing in this disease require preclinical validation in various mouse models that reflect this clinical heterogeneity. Using an expanded clinical sample set and mice modeling different mutations, we will test the hypothesis that mGlu7 levels may be differentially impacted in the context of distinct MECP2 mutations and determine if specific mutations underlie disease states most likely to exhibit efficacious and safe responses to mGlu7 PAMs or if mGlu7 PAMs will have utility across the entire mutation spectrum. Finally, we will perform biomarker studies that build upon our findings that Mecp2- deficient mice exhibit EEG spectral changes and reductions in REM sleep across the disease course. These findings mirror sleep abnormalities seen in RTT patients, suggesting that EEG represents a clinically translatable and noninvasive biomarker for the program.