Phenotypic profiling of mGlu₇ knockout mice reveals new implications for neurodevelopmental disorders

Abstract

Neurodevelopmental disorders are characterized by deficits in communication, cognition, attention, social behavior and/or motor control. Previous studies have pointed to the involvement of genes that regulate synaptic structure and function in the pathogenesis of these disorders. One such gene, GRM7, encodes the metabotropic glutamate receptor 7 (mGlu7), a G protein‐coupled receptor that regulates presynaptic neurotransmitter release. Mutations and polymorphisms in GRM7 have been associated with neurodevelopmental disorders in clinical populations; however, limited preclinical studies have evaluated mGlu7 in the context of this specific disease class. Here, we show that the absence of mGlu7 in mice is sufficient to alter phenotypes within the domains of social behavior, associative learning, motor function, epilepsy and sleep. Moreover, Grm7 knockout mice exhibit an attenuated response to amphetamine. These findings provide rationale for further investigation of mGlu7 as a potential therapeutic target for neurodevelopmental disorders such as idiopathic autism, attention deficit hyperactivity disorder and Rett syndrome.

A GRM7 mutation associated with developmental delay reduces mGlu7 expression and produces neurological phenotypes

“…Despite having about 50% protein expression, heterozygous Grm7 I154T/+ animals appear phenotypically normal, similar to our previous finding that Grm7 +/mice were not different from their wildtype littermates (12). The lack of phenotype in Grm7 I154T/+ mice suggests that I154T receptors do not have a significant dominant negative effect on WT mGlu7 receptors or other mGlu receptor subtypes in vivo.…”

“…Altogether, these data demonstrate that mGlu7 protein expression is highly regulated by quality-control mechanisms that recognize and degrade mGlu7-I154T receptors, and that the ECD plays a critical role in protein expression and trafficking. Consistent with an almost complete lack of mGlu7 protein expression, Grm7 I154T/I154T mice exhibit similar phenotypes as those reported in global Grm7 knockout mice, including deficits in motor coordination, impaired contextual fear memory and seizures (12)(13)(14). Importantly, these phenotypes parallel the clinical description of patients that are homozygous for this variant.…”

“…Interestingly, Grm7 knockout mice display several phenotypes that mirror those reported in the patients above. These include learning deficits, seizures, motor impairments and stereotyped paw clasping (12)(13)(14). Based on this phenotypic overlap, we hypothesized that the mGlu7-I154T substitution would lead to loss of receptor function.…”

“…Activation of mGlu7 can regulate release of glutamate and GABA, both of which have been shown to contribute to RTT-related phenotypes (28)(29)(30). Taken together with the fact that Grm7 knockout mice recapitulate phenotypes often observed in neurodevelopmental disorders (12), it was likely that GRM7 clinical variants would lead to loss-of-function of the mGlu7 receptor. However, this hypothesis had not been directly tested, leading us to determine the functional consequence of the mGlu7-I154T mutation.…”

Trans-Synaptic Regulation of Metabotropic Glutamate Receptors by Elfn Proteins in Health and Disease

“…Elfn1-KO mice exhibit hyperactivity and adult-onset (11 weeks or older) sensory-triggered epileptic seizures (Tomioka et al, 2014). In particular, the latter phenotype is similar to that of mGluR7-KO mice in that both Elfn1-and mGluR7-KO mice show myoclonic jerks and forelimb clonus that are sometimes tonic in nature, a Racine scale score of 2-5, and sign onset at around 10 weeks old (mGluR7 KO; Sansig et al, 2001;Fisher et al, 2020) or 11 weeks old (Elfn1 KO).…”