Therapeutic potential of metabotropic glutamate receptor 7 modulation in correcting cognitive deficits of...

Cognitive deficits in schizophrenia are a major predictor of patient functional outcome, and current treatments have limited efficacy in targeting this symptom domain. Glutamatergic dysfunction is hypothesized to contribute to cognitive impairments, and administration of N-methyl-d-aspartate (NMDA) receptor antagonists to both healthy humans and animals causes behavioral and cognitive deficits similar to those observed in patients with schizophrenia. In particular, hypofunction of NMDA receptors on GABAergic interneurons in the medial prefrontal cortex (mPFC) leads to excessive pyramidal cell activity and is a hypothesized mechanism underlying these deficits. As such, therapeutic modulation of glutamatergic and GABAergic release in PFC-associated circuits may correct cognitive impairments in schizophrenia. Metabotropic glutamate (mGlu) receptors have emerged as a promising strategy to target this symptom domain due to their widespread expression in relevant brain regions and their implications within the glutamate system. Group III mGlu receptors (mGlu_4/6/7/8) are G_i/o-coupled receptors which predominantly show presynaptic localization and are well-positioned to modulate both glutamatergic and GABAergic neurotransmission. In particular, mGlu₇ is widely expressed throughout the central nervous system, including expression on neurons within relevant PFC circuits. Interestingly, schizophrenia and other neuropsychiatric disorders characterized by cognitive deficits are associated with loss-of-function variants in GRM7, the gene encoding mGlu₇. Furthermore, both mGlu₇ potentiation and inhibition have shown efficacy in preclinical models of neurodevelopmental and neuropsychiatric disorders characterized by cognitive impairments. Therefore, mGlu₇ is proposed to be a viable therapeutic target to treat cognitive deficits driven by glutamatergic dysfunction in disorders including schizophrenia.