GRM7 encodes the metabotropic glutamate receptor 7 (mGlu7), a presynaptic, G protein-coupled glutamate receptor. It is essential for modulating neurotransmission, regulating synaptic plasticity and neurotransmitter release at presynaptic terminals [1,3,6]. It is involved in multiple neurodevelopmental pathways, and its dysfunction can lead to various neurodevelopmental disorders [1,3,5,7]. Genetic models, such as knockout mouse models, are valuable for studying its functions.

In mouse models, Grm7 knockdown increases neural progenitor cell proliferation, decreases terminal mitosis and neuronal differentiation, and leads to abnormal neuronal morphology. GRM7 regulates the phosphorylation of cyclic AMP response element-binding protein (CREB) and the expression of Yes-associated protein (YAP) through interaction with CaM, affecting early cortical development [5]. Pathogenic GRM7 mutations in rat embryo-derived cultured neurons lead to degradation of the mGlu7 protein, impair axon outgrowth via the mitogen-activated protein kinase (MAPK)-cAMP-protein kinase A (PKA) signaling pathway, and decrease the number of presynaptic terminals in mature neurons [6]. A GRM7 mutation (I154T) in mice results in reduced mGlu7 protein expression post-transcriptionally, leading to reduced motor coordination, deficits in contextual fear learning, and seizures [8].

In conclusion, GRM7 is crucial for normal neurodevelopment. Through model-based research, we've learned that it plays essential roles in processes like neuronal differentiation, axon outgrowth, and synaptic development. The study of GRM7 using knockout models has provided insights into its role in neurodevelopmental disorders such as epilepsy, microcephaly, cerebral atrophy, and conditions like autism spectrum disorder and attention deficit hyperactivity disorder [1,2,3,4,5,6,8].

References:

1. Freitas, Geanne A, Niswender, Colleen M. 2023. GRM7 gene mutations and consequences for neurodevelopment. In Pharmacology, biochemistry, and behavior, 225, 173546. doi:10.1016/j.pbb.2023.173546. https://pubmed.ncbi.nlm.nih.gov/37003303/

2. Januel, Louis, Chatron, Nicolas, Rivier-Ringenbach, Clotilde, de Sainte Agathe, Jean Madeleine, Lesca, Gaetan. 2023. GRM7-related disorder: five additional patients from three independent families and review of the literature. In European journal of medical genetics, 67, 104893. doi:10.1016/j.ejmg.2023.104893. https://pubmed.ncbi.nlm.nih.gov/38070825/

3. Zaki-Dizaji, Majid, Abazari, Mohammad Foad, Razzaghi, Hossein, Shkolnikov, Irene, Christie, Brian R. 2024. GRM7 deficiency, from excitotoxicity and neuroinflammation to neurodegeneration: Systematic review of GRM7 deficient patients. In Brain, behavior, & immunity - health, 39, 100808. doi:10.1016/j.bbih.2024.100808. https://pubmed.ncbi.nlm.nih.gov/38983774/

4. Marafi, Dana, Mitani, Tadahiro, Isikay, Sedat, Posey, Jennifer E, Lupski, James R. 2020. Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy. In Annals of clinical and translational neurology, 7, 610-627. doi:10.1002/acn3.51003. https://pubmed.ncbi.nlm.nih.gov/32286009/

5. Xia, Wenlong, Liu, YanLi, Jiao, Jianwei. 2015. GRM7 regulates embryonic neurogenesis via CREB and YAP. In Stem cell reports, 4, 795-810. doi:10.1016/j.stemcr.2015.03.004. https://pubmed.ncbi.nlm.nih.gov/25921811/

6. Song, Jae-Man, Kang, Minji, Park, Da-Ha, Lee, Sanghyeon, Suh, Young Ho. 2021. Pathogenic GRM7 Mutations Associated with Neurodevelopmental Disorders Impair Axon Outgrowth and Presynaptic Terminal Development. In The Journal of neuroscience : the official journal of the Society for Neuroscience, 41, 2344-2359. doi:10.1523/JNEUROSCI.2108-20.2021. https://pubmed.ncbi.nlm.nih.gov/33500274/

7. Gyetvai, Beatrix M, Vadasz, Csaba. 2025. Pleiotropic Effects of Grm7/GRM7 in Shaping Neurodevelopmental Pathways and the Neural Substrate of Complex Behaviors and Disorders. In Biomolecules, 15, . doi:10.3390/biom15030392. https://pubmed.ncbi.nlm.nih.gov/40149928/

8. Fisher, Nicole M, AlHashim, Aqeela, Buch, Aditi B, Gogliotti, Rocco G, Niswender, Colleen M. 2021. A GRM7 mutation associated with developmental delay reduces mGlu7 expression and produces neurological phenotypes. In JCI insight, 6, . doi:10.1172/jci.insight.143324. https://pubmed.ncbi.nlm.nih.gov/33476302/