Grin2a, also known as GluN2A or NR2A, encodes a subunit of the N-methyl-D-aspartate receptor (NMDAR). NMDARs are crucial for synaptic transmission, plasticity, and the development of neural circuits [4]. The glutamatergic system, in which Grin2a is involved, has long been postulated to play a role in the pathophysiology of various neurological and psychiatric disorders [1,3].

Heterozygous Grin2a mutant mice show large-scale gene expression changes across multiple brain regions and in different cell types, evidence of hypoactivity in the prefrontal cortex and hyperactivity in the hippocampus and striatum, elevated dopamine signaling in the striatum, altered cholesterol biosynthesis in astrocytes, reduction in glutamatergic receptor signaling proteins in the synapse, and an aberrant locomotor pattern [2]. Loss of Grin2a in mice causes a transient delay in the electrophysiological maturation of hippocampal parvalbumin interneurons, increased circuit excitability, and CA1 pyramidal cell output [5]. Mouse mutants in Grin2a also exhibit EEG abnormalities similar to those in schizophrenia patients, such as increased resting gamma power, attenuated auditory steady-state responses at gamma frequencies, and changes in sleep spindle density [6].

In conclusion, Grin2a is essential for the normal function of the NMDAR and is involved in key neural processes like synaptic plasticity and circuit development. Studies using Grin2a knockout mouse models have provided valuable insights into its role in diseases such as schizophrenia, epilepsy, and neurodevelopmental disorders, helping to uncover potential pathophysiologic mechanisms and identify biomarkers [2,5,6].

References:

1. Harrison, Paul J, Bannerman, David M. 2023. GRIN2A (NR2A): a gene contributing to glutamatergic involvement in schizophrenia. In Molecular psychiatry, 28, 3568-3572. doi:10.1038/s41380-023-02265-y. https://pubmed.ncbi.nlm.nih.gov/37736757/

2. Farsi, Zohreh, Nicolella, Ally, Simmons, Sean K, Levin, Joshua Z, Sheng, Morgan. 2023. Brain-region-specific changes in neurons and glia and dysregulation of dopamine signaling in Grin2a mutant mice. In Neuron, 111, 3378-3396.e9. doi:10.1016/j.neuron.2023.08.004. https://pubmed.ncbi.nlm.nih.gov/37657442/

3. Sheng, Xiao-Ming, Guan, Wei. . GRIN2A and Schizophrenia: Scientific Evidence and Biological Mechanisms. In Current neuropharmacology, 23, 621-634. doi:10.2174/011570159X327712241023084944. https://pubmed.ncbi.nlm.nih.gov/39501956/

4. Korinek, M, Candelas Serra, M, Abdel Rahman, Fes, Balik, A, Smejkalova, T. 2024. Disease-Associated Variants in GRIN1, GRIN2A and GRIN2B genes: Insights into NMDA Receptor Structure, Function, and Pathophysiology. In Physiological research, 73, S413-S434. doi:. https://pubmed.ncbi.nlm.nih.gov/38836461/

5. Camp, Chad R, Vlachos, Anna, Klöckner, Chiara, McBain, Chris J, Traynelis, Stephen F. 2023. Loss of Grin2a causes a transient delay in the electrophysiological maturation of hippocampal parvalbumin interneurons. In Communications biology, 6, 952. doi:10.1038/s42003-023-05298-9. https://pubmed.ncbi.nlm.nih.gov/37723282/

6. Herzog, Linnea E, Wang, Lei, Yu, Eunah, Pan, Jen Q, Sheng, Morgan. 2023. Mouse mutants in schizophrenia risk genes GRIN2A and AKAP11 show EEG abnormalities in common with schizophrenia patients. In Translational psychiatry, 13, 92. doi:10.1038/s41398-023-02393-7. https://pubmed.ncbi.nlm.nih.gov/36914641/