Metabotropic Glutamate Receptor 7: A New Therapeutic Target in Neurodevelopmental Disorders

Abstract

Neurodevelopmental disorders (NDDs) are characterized by a wide range of symptoms including delayed speech, intellectual disability, motor dysfunction, social deficits, breathing problems, structural abnormalities, and epilepsy. Unfortunately, current treatment strategies are limited and innovative new approaches are sorely needed to address these complex diseases. The metabotropic glutamate receptors are a class of G protein-coupled receptors that act to modulate neurotransmission across many brain structures. They have shown great promise as drug targets for numerous neurological and psychiatric diseases. Moreover, the development of subtype-selective allosteric modulators has allowed detailed studies of each receptor subtype. Here, we focus on the metabotropic glutamate receptor 7 (mGlu7) as a potential therapeutic target for NDDs. mGlu7 is expressed widely throughout the brain in regions that correspond to the symptom domains listed above and has established roles in synaptic physiology and behavior. Single nucleotide polymorphisms and mutations in the GRM7 gene have been associated with idiopathic autism and other NDDs in patients. In rodent models, existing literature suggests that decreased mGlu7 expression and/or function may lead to symptoms that overlap with those of NDDs. Furthermore, potentiation of mGlu7 activity has shown efficacy in a mouse model of Rett syndrome. In this review, we summarize current findings that provide rationale for the continued development of mGlu7 modulators as potential therapeutics.

Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy

“…Additionally, there are ample neuropharmacological studies focusing on the potential for using allosteric modulators of mGluRs in the treatment of neurological diseases and epilepsy 52,53 . Selective positive allosteric modulators (PAMs) for group III mGluRs have been recently developed, potentially representing novel targeted and personalized therapy in partial mGluR7 LoF (hypomorph alleles).…”

20 Years an Orphan: Is GPR84 a Plausible Medium-Chain Fatty Acid-Sensing Receptor?

“…PLAUSIBILITY OF MCFA-GPR84 DE-ORPHANIZATION 1927 serving to inhibit further glutamate release (Fisher et al, 2018). Likewise, a recently deorphanized example is the HCA 2 receptor that has a 700 mM affinity for b-hydroxybutyrate, which reaches these levels during fasting or ketogenesis, and then acts to prevent further lipolysis (Offermanns and Schwaninger, 2015).…”

Calbindin Deficits May Underlie Dissociable Effects of 5-HT6 and mGlu7 Antagonists on Glutamate and Cognition in a Dual-Hit Neurodevelopmental Model for Schizophrenia

“…The relationship between mGlu 7 and memory is also complex, with the mGlu 7 -negative modulator MMPIP both impairing NOD in normal mice [58] and recently proposed as a putative antipsychotic due to its ability to reverse acute MK-801-induced hyperactivity and cognitive deficits in mouse NOD and rat spatial delayed alternation tests [56]. It has been suggested mGlu 7 may represent a new treatment target for neurodevelopmental disorders [134], and current neurochemical and behavioral findings certainly appear to justify continued preclinical evaluation of mGlu 7 allosteric antagonists against a broader variety of PCP-Iso-induced cognitive impairments. This is important since the NOD test of visual recognition memory performed here has translational relevance to only one of several cognitive domains impaired in schizophrenia [45].…”