Therapeutic Potential for Metabotropic Glutamate Receptor 7 Modulators in Cognitive Disorders

Metabotropic glutamate receptor 7 (mGlu₇) is the most highly conserved and abundantly expressed mGlu receptor in the human brain. The presynaptic localization of mGlu₇, coupled with its low affinity for its endogenous agonist, glutamate, are features that contribute to the receptor's role in modulating neuronal excitation and inhibition patterns, including long-term potentiation, in various brain regions. These characteristics suggest that mGlu₇ modulation may serve as a novel therapeutic strategy in disorders of cognitive dysfunction, including neurodevelopmental disorders that cause impairments in learning, memory, and attention. Primary mutations in the GRM7 gene have recently been identified as novel causes of neurodevelopmental disorders, and these patients exhibit profound intellectual and cognitive disability. Pharmacological tools, such as agonists, antagonists, and allosteric modulators, have been the mainstay for targeting mGlu₇ in its endogenous homodimeric form to probe effects of its function and modulation in disease models. However, recent research has identified diversity in dimerization, as well as trans-synaptic interacting proteins, that also play a role in mGlu₇ signaling and pharmacological properties. These novel findings represent exciting opportunities in the field of mGlu receptor drug discovery and highlight the importance of further understanding the functions of mGlu₇ in complex neurologic conditions at both the molecular and physiologic levels. SIGNIFICANCE STATEMENT: Proper expression and function of mGlu₇ is essential for learning, attention, and memory formation at the molecular level within neural circuits. The pharmacological targeting of mGlu₇ is undergoing a paradigm shift by incorporating an understanding of receptor interaction with other cis- and trans- acting synaptic proteins, as well as various intracellular signaling pathways. Based upon these new findings, mGlu₇'s potential as a drug target in the treatment of cognitive disorders and learning impairments is primed for exploration.