Therapeutic potential of metabotropic glutamate receptor 7 modulation in correcting cognitive deficits of schizophrenia
4 affiliations
- 1Vanderbilt Brain Institute, United States
- 2Department of Pharmacology and Warren Center for Neuroscience Drug Discovery, United States
- 3Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN, 37232, United States
- 4Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN 37232, United States
Abstract
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 (mGlu4/6/7/8) are Gi/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.
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BibTeX
@article{harris2026therapeutic,
title = {{Therapeutic potential of metabotropic glutamate receptor 7 modulation in correcting cognitive deficits of schizophrenia}},
author = {Niki M. Harris and Kimberly M. Holter and Colleen M. Niswender},
journal = {Schizophrenia research},
year = {2026},
month = jun,
doi = {10.1016/j.schres.2026.06.012},
url = {https://doi.org/10.1016/j.schres.2026.06.012},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Therapeutic potential of metabotropic glutamate receptor 7 modulation in correcting cognitive deficits of schizophrenia
AU - Niki M. Harris
AU - Kimberly M. Holter
AU - Colleen M. Niswender
PY - 2026
DA - 2026/06/17
JO - Schizophrenia research
DO - 10.1016/j.schres.2026.06.012
UR - https://doi.org/10.1016/j.schres.2026.06.012
AB - 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 (mGlu4/6/7/8) are Gi/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.
SN - 0920-9964
SN - 1573-2509
ER -