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.
Highlights
Neurodevelopmental disorders are a group of conditions that present in early life and are characterized by the failure to meet typical developmental milestones
We focus on the metabotropic glutamate receptor 7 as a potential therapeutic target for Neurodevelopmental disorders (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
We focus on the metabotropic glutamate receptor 7, a G protein-coupled receptor (GPCR) that serves as an important regulator of synaptic transmission and plasticity
Summary
Neurodevelopmental disorders are a group of conditions that present in early life and are characterized by the failure to meet typical developmental milestones. This would suggest that AMN082 can act as a functional antagonist by decreasing surface expression and, receptor signaling This hypothesis is further supported by the ability of the mGlu antagonist XAP044 to block LTP within the amygdala, inhibit acquisition of conditioned fear, and reduce anxiety-like behavior (Gee et al, 2014). Masugi et al (1999) and Goddyn et al (2008, 2015) demonstrated that Grm7−/− mice exhibit less freezing than wild-type animals in cued and contextual fear conditioning paradigms Together, these results indicate a role for mGlu in aversion learning, and suggest that the loss of mGlu causes impairments in these learning paradigms. Grm7−/− mice performed to wild-type animals after increased training and in un-cued trials (Callaerts-Vegh et al, 2006) Together, these data demonstrate that mGlu may play specific roles in tasks involving working and spatial memory. MeCP2 is involved in prenatal and postnatal development
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