{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n The α5 subunit of the γ‐aminobutyric acid type A (GABA_A) receptor (GABRA5) plays a pivotal role in regulating neuronal excitability and synaptic plasticity. In the hippocampus and cortex, α5‐containing receptors mediate a prominent form of tonic inhibition that sets the threshold for long‐term potentiation and modulates memory encoding."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Dysregulation of GABRA5 function has been implicated in several neuropsychiatric and neurological conditions. Functional studies of rare de novo mutations in GABRA5 have demonstrated that altered receptor properties—including increased sensitivity to GABA and reduced maximal currents due to enhanced desensitization—can contribute to early‐onset epilepsy and developmental delay."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Furthermore, upregulation of α5‐GABA_A receptor expression observed during inflammatory insults or following chronic ketamine administration has been associated with impairments in hippocampal and prefrontal memory function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Genetic association studies further support its involvement in mood and anxiety disorders; variation in the GABRA5 gene has been linked to bipolar disorder and panic disorder, and reduced expression in specific brain regions has been noted in schizophrenia."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "10"}]}, {"type": "t", "text": " In addition, evidence from developmental studies indicates that GABRA5‐mediated signaling is critical for proper neuronal migration and dendritic maturation in the hippocampus, with partial loss of function leading to marked deficits that can be ameliorated by modulation of intracellular pathways such as those involving Cdk5."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " Collectively, these findings underscore the central role of GABRA5 in maintaining inhibitory tone, orchestrating synaptic plasticity, and ensuring cognitive integrity; its dysregulation may thus contribute to a broad spectrum of neurodevelopmental, epileptic, and psychiatric disorders.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Joseph Glykys, Edward O Mann, Istvan Mody "}, {"type": "b", "children": [{"type": "t", "text": "Which GABA(A) receptor subunits are necessary for tonic inhibition in the hippocampus?"}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1523/JNEUROSCI.4751-07.2008"}], "href": "https://doi.org/10.1523/JNEUROSCI.4751-07.2008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18256262"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18256262"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Loren J Martin, Agnieszka A Zurek, John F MacDonald, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Alpha5GABAA receptor activity sets the threshold for long-term potentiation and constrains hippocampus-dependent memory."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1523/JNEUROSCI.4209-09.2010"}], "href": "https://doi.org/10.1523/JNEUROSCI.4209-09.2010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20392949"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20392949"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Kameryn M Butler, Olivia A Moody, Elisabeth Schuler, et al. "}, {"type": "b", "children": [{"type": "t", "text": "De novo variants in GABRA2 and GABRA5 alter receptor function and contribute to early-onset epilepsy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/brain/awy171"}], "href": "https://doi.org/10.1093/brain/awy171"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29961870"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29961870"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Ciria C Hernandez, Wenshu XiangWei, Ningning Hu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Altered inhibitory synapses in de novo GABRA5 and GABRA1 mutations associated with early onset epileptic encephalopathies."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/brain/awz123"}], "href": "https://doi.org/10.1093/brain/awz123"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31056671"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31056671"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Dian-Shi Wang, Agnieszka A Zurek, Irene Lecker, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Memory deficits induced by inflammation are regulated by α5-subunit-containing GABAA receptors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2012.08.022"}], "href": "https://doi.org/10.1016/j.celrep.2012.08.022"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22999935"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22999935"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Sijie Tan, John A Rudd, David T Yew "}, {"type": "b", "children": [{"type": "t", "text": "Gene expression changes in GABA(A) receptors and cognition following chronic ketamine administration in mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0021328"}], "href": "https://doi.org/10.1371/journal.pone.0021328"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21712993"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21712993"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "N Craddock, L Jones, I R Jones, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Strong genetic evidence for a selective influence of GABAA receptors on a component of the bipolar disorder phenotype."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Psychiatry (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/mp.2008.66"}], "href": "https://doi.org/10.1038/mp.2008.66"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19078961"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19078961"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Kyohei Otani, Hiroshi Ujike, Yuji Tanaka, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The GABA type A receptor alpha5 subunit gene is associated with bipolar I disorder."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurosci Lett (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neulet.2005.02.010"}], "href": "https://doi.org/10.1016/j.neulet.2005.02.010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15882799"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15882799"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Laura M Hodges, Abby J Fyer, Myrna M Weissman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Evidence for linkage and association of GABRB3 and GABRA5 to panic disorder."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neuropsychopharmacology (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/npp.2014.92"}], "href": "https://doi.org/10.1038/npp.2014.92"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24755890"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24755890"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Greg C Bristow, John A Bostrom, Vahram Haroutunian, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sex differences in GABAergic gene expression occur in the anterior cingulate cortex in schizophrenia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Schizophr Res (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.schres.2015.01.025"}], "href": "https://doi.org/10.1016/j.schres.2015.01.025"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25660468"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25660468"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Francine Deprez, Fabia Vogt, Amalia Floriou-Servou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Partial inactivation of GABAA receptors containing the α5 subunit affects the development of adult-born dentate gyrus granule cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Neurosci (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/ejn.13329"}], "href": "https://doi.org/10.1111/ejn.13329"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27364953"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27364953"}]}]}]}