Grm2, encoding metabotropic glutamate receptor 2 (mGluR2), is highly expressed in hippocampal dentate granule cells (DGCs) and plays a crucial role in regulating synaptic transmission and hippocampal functions [1]. It is involved in modulating the MEK/ERK1/2 pathway, which is essential for normal neuronal development and integration [1]. Bacterial microcompartments (BMCs) from Klebsiella pneumoniae GRM2 locus are also associated with Grm2, involved in enzymatic processes like carbon fixation and choline degradation [2,3,5].

In mice, lack of Grm2 in adult-born DGCs leads to developmental defects of DGCs and impairs hippocampus-dependent cognitive functions [1]. Knockdown of Grm2 decreases b/c-Raf kinases but paradoxically over-activates the MEK/ERK1/2 pathway, and inhibiting MEK can ameliorate the developmental defects [1]. In Hannover-derived Wistar rats, a cys407* Grm2 mutation is prevalent in some strains, and rats with this mutation show altered emotionality, impulsivity, risk-related behaviors, and increased voluntary alcohol intake [4]. In the Japanese population, GRM2 may be involved in the pathophysiology of methamphetamine-induced psychosis but not schizophrenia [6]. GRM2/3 double knockout mice show abnormal hippocampus-dependent memory, with deficits in appetitively motivated spatial tasks but normal performance in aversively motivated ones, suggesting a role for group II mGluRs at the interface of arousal and cognition [7].

In summary, Grm2 is essential for the development and functional integration of adult-born DGCs in the hippocampus through regulating the MEK/ERK1/2 pathway. Mouse models with Grm2 knockout or mutation have provided insights into its role in cognitive functions, emotional and risk-related behaviors, as well as in methamphetamine-induced psychosis. These findings highlight the importance of Grm2 in understanding certain neurological and psychiatric conditions [1,4,6,7].

References:

1. Ma, Jiao, Hu, Zhechun, Yue, Huimin, Gu, Yan, Wang, Lang. 2023. GRM2 Regulates Functional Integration of Adult-Born DGCs by Paradoxically Modulating MEK/ERK1/2 Pathway. In The Journal of neuroscience : the official journal of the Society for Neuroscience, 43, 2822-2836. doi:10.1523/JNEUROSCI.1886-22.2023. https://pubmed.ncbi.nlm.nih.gov/36878727/

2. Cesle, Eva Emilija, Filimonenko, Anatolij, Tars, Kaspars, Kalnins, Gints. 2021. Variety of size and form of GRM2 bacterial microcompartment particles. In Protein science : a publication of the Protein Society, 30, 1035-1043. doi:10.1002/pro.4069. https://pubmed.ncbi.nlm.nih.gov/33763934/

3. Kalnins, Gints, Cesle, Eva-Emilija, Jansons, Juris, Filimonenko, Anatolij, Tars, Kaspars. 2020. Encapsulation mechanisms and structural studies of GRM2 bacterial microcompartment particles. In Nature communications, 11, 388. doi:10.1038/s41467-019-14205-y. https://pubmed.ncbi.nlm.nih.gov/31959751/

4. Wood, Christian M, Nicolas, Celine S, Choi, Sun-Lim, Robinson, Emma S J, Lodge, David. 2016. Prevalence and influence of cys407* Grm2 mutation in Hannover-derived Wistar rats: mGlu2 receptor loss links to alcohol intake, risk taking and emotional behaviour. In Neuropharmacology, 115, 128-138. doi:10.1016/j.neuropharm.2016.03.020. https://pubmed.ncbi.nlm.nih.gov/26987983/

5. Česle, Eva Emi Lija, Ta Rs, Kaspars, Jansons, Juris, Kalniņš, Gints. 2023. Modulation of Hybrid GRM2-type Bacterial Microcompartment Shells through BMC-H Shell Protein Fusion and Incorporation of Non-native BMC-T Shell Proteins. In ACS synthetic biology, 12, 3275-3286. doi:10.1021/acssynbio.3c00281. https://pubmed.ncbi.nlm.nih.gov/37937366/

6. Tsunoka, Tomoko, Kishi, Taro, Kitajima, Tsuyoshi, Ozaki, Norio, Iwata, Nakao. 2010. Association analysis of GRM2 and HTR2A with methamphetamine-induced psychosis and schizophrenia in the Japanese population. In Progress in neuro-psychopharmacology & biological psychiatry, 34, 639-44. doi:10.1016/j.pnpbp.2010.03.002. https://pubmed.ncbi.nlm.nih.gov/20211215/

7. Lyon, Louisa, Burnet, Philip W J, Kew, James N C, Harrison, Paul J, Bannerman, David M. 2011. Fractionation of spatial memory in GRM2/3 (mGlu2/mGlu3) double knockout mice reveals a role for group II metabotropic glutamate receptors at the interface between arousal and cognition. In Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 36, 2616-28. doi:10.1038/npp.2011.145. https://pubmed.ncbi.nlm.nih.gov/21832989/