{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n The gene GABRA4 encodes the α4 subunit of the γ‐aminobutyric acid type A (GABA_A) receptor, a key mediator of inhibitory neurotransmission in the central nervous system. Genetic association studies have implicated variation in GABRA4 in several neuropsychiatric and substance‐related disorders. For example, polymorphisms in GABRA4 have been linked to nicotine dependence ("}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "), whereas independent investigations in autism spectrum disorder have reported noncoding single‐nucleotide variants in GABRA4, alone or interacting with GABRB1, to be associated with increased disease risk ("}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": "). In addition, alterations in GABRA4 are observed in bipolar and schizoaffective disorders ("}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "), underscoring its role in a broad range of neuropsychiatric phenotypes.\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Functional studies further demonstrate that the expression and regulation of GABRA4 are dynamic and context dependent. Brain‐derived neurotrophic factor has been shown to increase the abundance of α4‐containing receptors through pathways distinct from those affecting other subunits ("}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "). Analysis of the promoter region of the mouse GABRA4 gene revealed multiple transcription initiation sites and critical roles for Sp family transcription factors in driving its neuronal expression ("}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "). Moreover, during alcohol withdrawal key microRNAs are induced that downregulate Gabra4 expression, highlighting an additional level of post‐transcriptional modulation ("}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ").\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n The interplay of GABRA4 with other GABA_A receptor subunits—particularly through gene–gene interactions with GABRB1—appears to modulate the excitatory/inhibitory balance that is critical for normal neural network development and function. Such interactions are thought to contribute to the synaptic dysfunction observed in autism and may extend to other disorders of neural regulation. Collectively, these findings underscore a multifaceted role for GABRA4 in modulating inhibitory synaptic transmission, neuronal excitability, and plasticity in health and disease.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Scott F Saccone, Anthony L Hinrichs, Nancy L Saccone, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddl438"}], "href": "https://doi.org/10.1093/hmg/ddl438"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17135278"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17135278"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Arpana Agrawal, Michele L Pergadia, Sumitra Balasubramanian, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Further evidence for an association between the gamma-aminobutyric acid receptor A, subunit 4 genes on chromosome 4 and Fagerström Test for Nicotine Dependence."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Addiction (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1360-0443.2008.02445.x"}], "href": "https://doi.org/10.1111/j.1360-0443.2008.02445.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19207358"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19207358"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "D Q Ma, P L Whitehead, M M Menold, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1086/433195"}], "href": "https://doi.org/10.1086/433195"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16080114"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16080114"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Ann L Collins, Deqiong Ma, Patrice L Whitehead, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Investigation of autism and GABA receptor subunit genes in multiple ethnic groups."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurogenetics (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10048-006-0045-1"}], "href": "https://doi.org/10.1007/s10048-006-0045-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16770606"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16770606"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Carla V Sesarini, Lucas Costa, Nora Grañana, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association between GABA(A) receptor subunit polymorphisms and autism spectrum disorder (ASD)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Psychiatry Res (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.psychres.2015.07.077"}], "href": "https://doi.org/10.1016/j.psychres.2015.07.077"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26239769"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26239769"}]}, {"type": "r", "ref": 6, "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": 7, "children": [{"type": "t", "text": "Ingrid V Lund, Yinghui Hu, YogendraSinh H Raol, et al. "}, {"type": "b", "children": [{"type": "t", "text": "BDNF selectively regulates GABAA receptor transcription by activation of the JAK/STAT pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Signal (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/scisignal.1162396"}], "href": "https://doi.org/10.1126/scisignal.1162396"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18922788"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18922788"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Limei Ma, Lihua Song, Gina E Radoi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transcriptional regulation of the mouse gene encoding the alpha-4 subunit of the GABAA receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M406827200"}], "href": "https://doi.org/10.1074/jbc.M406827200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15265862"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15265862"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Afshin Paydar, Boyoung Lee, Gireesh Gangadharan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Extrasynaptic GABAA receptors in mediodorsal thalamic nucleus modulate fear extinction learning."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Brain (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1756-6606-7-39"}], "href": "https://doi.org/10.1186/1756-6606-7-39"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24886120"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24886120"}]}]}]}