Gabra5, encoding the α5 subunit of the GABAA receptor, is crucial for inhibitory neurotransmission in the central nervous system [3,5,6]. GABAA receptors, ligand-gated chloride channels, are key in regulating neuronal excitation-inhibition balance, with Gabra5-containing receptors involved in multiple pathways related to behaviors and physiological functions [3,5,6]. Genetic models, like KO mouse models, are valuable for studying Gabra5 function.

In KO mouse models, ablation of Gabra5 led to decreased rearing behavior and fecal corticosterone metabolite levels, suggesting lower anxiety and stress response [4]. In diet-induced obesity mouse models, chemogenetic inhibition or gene silencing of Gabra5 in the lateral hypothalamic area (LHA) had opposite effects on weight gain, with GABRA5-positive neurons in LHA suppressing fat accumulation [1]. In POMC neuron-specific Gabra5 knockdown mice, male mice showed increased POMC neuron firing frequency and improved glucose tolerance, revealing a sexually dimorphic role in glucose balance [2]. In epilepsy-related research, de novo mutations in Gabra5 were found in patients with developmental and epileptic encephalopathy, and mutant Gabra5-containing GABAA receptors had reduced function [5,6].

In summary, Gabra5 is essential for inhibitory neurotransmission and is involved in various biological processes. Mouse models, especially KO and tissue-specific knockdown models, have revealed its role in obesity, glucose balance, anxiety-like behavior, and epilepsy. Understanding Gabra5 function through these models may provide insights into the mechanisms of related diseases and potential therapeutic targets.

References:

1. Sa, Moonsun, Yoo, Eun-Seon, Koh, Wuhyun, Sohn, Jong-Woo, Lee, C Justin. 2023. Hypothalamic GABRA5-positive neurons control obesity via astrocytic GABA. In Nature metabolism, 5, 1506-1525. doi:10.1038/s42255-023-00877-w. https://pubmed.ncbi.nlm.nih.gov/37653043/

2. Pei, Zhou, He, Yang, Bean, Jonathan C, Xu, Yong, Wang, Chunmei. 2022. Gabra5 plays a sexually dimorphic role in POMC neuron activity and glucose balance. In Frontiers in endocrinology, 13, 889122. doi:10.3389/fendo.2022.889122. https://pubmed.ncbi.nlm.nih.gov/36120438/

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. Syding, Linn Amanda, Kubik-Zahorodna, Agnieszka, Reguera, David Pajuelo, Turecek, Rostislav, Sedlacek, Radislav. 2023. Ablation of Gabra5 Influences Corticosterone Levels and Anxiety-like Behavior in Mice. In Genes, 14, . doi:10.3390/genes14020285. https://pubmed.ncbi.nlm.nih.gov/36833213/

5. Boonsimma, Ponghatai, Suwannachote, Sirorat, Phokaew, Chureerat, Suphapeetiporn, Kanya, Shotelersuk, Vorasuk. 2020. A case of GABRA5-related developmental and epileptic encephalopathy with response to a combination of antiepileptic drugs and a GABAering agent. In Brain & development, 42, 546-550. doi:10.1016/j.braindev.2020.03.005. https://pubmed.ncbi.nlm.nih.gov/32249079/

6. Hernandez, Ciria C, XiangWei, Wenshu, Hu, Ningning, Jiang, Yuwu, Macdonald, Robert L. . Altered inhibitory synapses in de novo GABRA5 and GABRA1 mutations associated with early onset epileptic encephalopathies. In Brain : a journal of neurology, 142, 1938-1954. doi:10.1093/brain/awz123. https://pubmed.ncbi.nlm.nih.gov/31056671/