GRIA1, encoding the GluA1 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors, is a crucial gene. AMPA receptors are ligand-gated ion channels that act as excitatory receptors for the neurotransmitter L-glutamate, playing a vital role in excitatory neurotransmission in the brain [1,3].

Functional studies on individuals with GRIA1 variants, including those with de novo missense and nonsense variants, have shown that these can lead to a neurodevelopmental disorder mostly affecting cognition and speech [3]. The p.(Ala636Thr) variant, for example, is recurrent and is associated with motor and/or language delay, intellectual disability, behavioral and psychiatric comorbidities, hypotonia and epilepsy [1]. In addition, Xenopus gria1 CRISPR-Cas9 F0 models, a form of in vivo study, showed transient motor deficits, an intermittent seizure phenotype, and significant working memory impairment in mutants, indicating the importance of GRIA1 in these functions [3]. Sevoflurane preconditioning, which downregulates GRIA1 expression, can attenuate cerebral ischemia-reperfusion-induced neuronal injury, suggesting GRIA1's role in this pathological process [2].

In conclusion, GRIA1 is essential for normal brain function, especially in excitatory neurotransmission. Research using genetic models like the Xenopus gria1 models has revealed its role in neurodevelopmental disorders and neurological injury. Understanding GRIA1 can provide insights into the mechanisms of these diseases and potentially lead to new therapeutic strategies.

References:

1. Tvergaard, Nicolai Kohring, Tkemaladze, Tinatin, Stödberg, Tommy, Tümer, Zeynep, Bayat, Allan. 2024. Unraveling GRIA1 neurodevelopmental disorders: Lessons learned from the p.(Ala636Thr) variant. In Clinical genetics, 106, 427-436. doi:10.1111/cge.14577. https://pubmed.ncbi.nlm.nih.gov/38890806/

2. Li, Ye, Liang, Zhi, Lei, Shuyan, Ma, Kai, Chi, Kui. 2023. Sevoflurane Preconditioning Downregulates GRIA1 Expression to Attenuate Cerebral Ischemia-Reperfusion-Induced Neuronal Injury. In Neurotoxicity research, 41, 29-40. doi:10.1007/s12640-022-00620-5. https://pubmed.ncbi.nlm.nih.gov/36595163/

3. Ismail, Vardha, Zachariassen, Linda G, Godwin, Annie, Kristensen, Anders S, Baralle, Diana. 2022. Identification and functional evaluation of GRIA1 missense and truncation variants in individuals with ID: An emerging neurodevelopmental syndrome. In American journal of human genetics, 109, 1217-1241. doi:10.1016/j.ajhg.2022.05.009. https://pubmed.ncbi.nlm.nih.gov/35675825/