Gabra2, encoding the GABAA α2 subunit, is a gene of significant importance. The GABAA receptor is crucial in the central nervous system as it mediates the inhibitory neurotransmission of gamma-aminobutyric acid (GABA), a key inhibitory neurotransmitter in the brain. This process is involved in maintaining the balance between neuronal excitation and inhibition, which is essential for normal brain function [3].

In mouse models, Gabra2 has been shown to be a genetic modifier in several disease conditions. In Dravet syndrome, where mice with heterozygous deletion of Scn1a (Scn1a+/-) model the disease, a B6-specific single nucleotide deletion within Gabra2 lowers its mRNA and protein levels. Repair of this deletion in B6 mice restored normal Gabra2 expression, increased the abundance of α2-containing GABAA receptors in hippocampal synapses, and rescued epilepsy phenotypes of Scn1a+/- mice, validating Gabra2 as a genetic modifier of Dravet syndrome [1]. Similarly, in Scn8a encephalopathy mouse models, the C57BL/6J strain carries a splice site mutation in Gabra2 that reduces its expression. Homozygosity for this hypomorphic variant is associated with early seizure onset and short lifespan, while the protective wild-type allele from the SJL/J strain delays seizure onset and extends lifespan. Correction of the Gabra2 splice site variant in C57BL/6J mice restores transcript abundance, increases the age of seizure onset, and extends survival of Scn8a mutant mice [2,4].

In conclusion, Gabra2 plays a vital role in modulating inhibitory neurotransmission through its encoding of the GABAA α2 subunit. Mouse models, especially those with gene knock-out or allele corrections related to Gabra2, have been instrumental in revealing its role in epilepsy-related disorders such as Dravet syndrome and Scn8a encephalopathy. These findings suggest that enhancing the function of α2-containing GABAA receptors could be a potential treatment strategy for these diseases [1].

References:

1. Hawkins, Nicole A, Nomura, Toshihiro, Duarte, Samantha, Contractor, Anis, Kearney, Jennifer A. 2021. Gabra2 is a genetic modifier of Dravet syndrome in mice. In Mammalian genome : official journal of the International Mammalian Genome Society, 32, 350-363. doi:10.1007/s00335-021-09877-1. https://pubmed.ncbi.nlm.nih.gov/34086081/

2. Yu, Wenxi, Hill, Sophie F, Xenakis, James G, Wagnon, Jacy L, Meisler, Miriam H. 2020. Gabra2 is a genetic modifier of Scn8a encephalopathy in the mouse. In Epilepsia, 61, 2847-2856. doi:10.1111/epi.16741. https://pubmed.ncbi.nlm.nih.gov/33140451/

3. Feng, Yan, Wei, Zi-Han, Liu, Chao, Zhang, Chu-Chu, Deng, Yan-Chun. 2022. Genetic variations in GABA metabolism and epilepsy. In Seizure, 101, 22-29. doi:10.1016/j.seizure.2022.07.007. https://pubmed.ncbi.nlm.nih.gov/35850019/

4. Yu, Wenxi, Mulligan, Megan K, Williams, Robert W, Meisler, Miriam H. 2021. Correction of the hypomorphic Gabra2 splice site variant in mouse strain C57BL/6J modifies the severity of Scn8a encephalopathy. In HGG advances, 3, 100064. doi:10.1016/j.xhgg.2021.100064. https://pubmed.ncbi.nlm.nih.gov/35047853/