{"title":"新生儿大脑中 GABA 能抑制性中间神经元对胆红素神经毒性的选择脆弱性","authors":"Li-Na Gong, Han-Wei Liu, Ke Lai, Zhen Zhang, Lin-Fei Mao, Zhen-Qi Liu, Ming-Xian Li, Xin-Lu Yin, Min Liang, Hai-Bo Shi, Lu-Yang Wang, Shan-Kai Yin","doi":"10.1523/JNEUROSCI.0442-24.2024","DOIUrl":null,"url":null,"abstract":"<p><p>Hyperbilirubinemia (HB) is a key risk factor for hearing loss in neonates, particularly premature infants. Here, we report that bilirubin (BIL)-dependent cell death in the auditory brainstem of neonatal mice of both sexes is significantly attenuated by ZD7288, a blocker for hyperpolarization-activated cyclic nucleotide-gated (HCN) channel-mediated current (<i>I</i> <sub>h</sub>), or by genetic deletion of HCN1. GABAergic inhibitory interneurons predominantly express HCN1, on which BIL selectively acts to increase their intrinsic excitability and mortality by enhancing HCN1 activity and Ca<sup>2+</sup>-dependent membrane targeting. Chronic BIL elevation in neonatal mice in vivo increases the fraction of spontaneously active interneurons and their firing frequency, <i>I</i> <sub>h</sub>, and death, compromising audition at the young adult stage in HCN1<sup>+/+</sup>, but not in HCN1<sup>-/-</sup> genotype. We conclude that HB preferentially targets HCN1 to injure inhibitory interneurons, fueling a feedforward loop in which lessening inhibition cascades hyperexcitability, Ca<sup>2+</sup> overload, neuronal death, and auditory impairments. These findings rationalize HCN1 as a potential target for managing HB encephalopathy.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.4000,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Selective Vulnerability of GABAergic Inhibitory Interneurons to Bilirubin Neurotoxicity in the Neonatal Brain.\",\"authors\":\"Li-Na Gong, Han-Wei Liu, Ke Lai, Zhen Zhang, Lin-Fei Mao, Zhen-Qi Liu, Ming-Xian Li, Xin-Lu Yin, Min Liang, Hai-Bo Shi, Lu-Yang Wang, Shan-Kai Yin\",\"doi\":\"10.1523/JNEUROSCI.0442-24.2024\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Hyperbilirubinemia (HB) is a key risk factor for hearing loss in neonates, particularly premature infants. Here, we report that bilirubin (BIL)-dependent cell death in the auditory brainstem of neonatal mice of both sexes is significantly attenuated by ZD7288, a blocker for hyperpolarization-activated cyclic nucleotide-gated (HCN) channel-mediated current (<i>I</i> <sub>h</sub>), or by genetic deletion of HCN1. GABAergic inhibitory interneurons predominantly express HCN1, on which BIL selectively acts to increase their intrinsic excitability and mortality by enhancing HCN1 activity and Ca<sup>2+</sup>-dependent membrane targeting. Chronic BIL elevation in neonatal mice in vivo increases the fraction of spontaneously active interneurons and their firing frequency, <i>I</i> <sub>h</sub>, and death, compromising audition at the young adult stage in HCN1<sup>+/+</sup>, but not in HCN1<sup>-/-</sup> genotype. We conclude that HB preferentially targets HCN1 to injure inhibitory interneurons, fueling a feedforward loop in which lessening inhibition cascades hyperexcitability, Ca<sup>2+</sup> overload, neuronal death, and auditory impairments. These findings rationalize HCN1 as a potential target for managing HB encephalopathy.</p>\",\"PeriodicalId\":50114,\"journal\":{\"name\":\"Journal of Neuroscience\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.4000,\"publicationDate\":\"2024-11-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Neuroscience\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1523/JNEUROSCI.0442-24.2024\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Neuroscience","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1523/JNEUROSCI.0442-24.2024","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
Selective Vulnerability of GABAergic Inhibitory Interneurons to Bilirubin Neurotoxicity in the Neonatal Brain.
Hyperbilirubinemia (HB) is a key risk factor for hearing loss in neonates, particularly premature infants. Here, we report that bilirubin (BIL)-dependent cell death in the auditory brainstem of neonatal mice of both sexes is significantly attenuated by ZD7288, a blocker for hyperpolarization-activated cyclic nucleotide-gated (HCN) channel-mediated current (Ih), or by genetic deletion of HCN1. GABAergic inhibitory interneurons predominantly express HCN1, on which BIL selectively acts to increase their intrinsic excitability and mortality by enhancing HCN1 activity and Ca2+-dependent membrane targeting. Chronic BIL elevation in neonatal mice in vivo increases the fraction of spontaneously active interneurons and their firing frequency, Ih, and death, compromising audition at the young adult stage in HCN1+/+, but not in HCN1-/- genotype. We conclude that HB preferentially targets HCN1 to injure inhibitory interneurons, fueling a feedforward loop in which lessening inhibition cascades hyperexcitability, Ca2+ overload, neuronal death, and auditory impairments. These findings rationalize HCN1 as a potential target for managing HB encephalopathy.
期刊介绍:
JNeurosci (ISSN 0270-6474) is an official journal of the Society for Neuroscience. It is published weekly by the Society, fifty weeks a year, one volume a year. JNeurosci publishes papers on a broad range of topics of general interest to those working on the nervous system. Authors now have an Open Choice option for their published articles