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

IF 4.4 2区 医学 Q1 NEUROSCIENCES
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
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引用次数: 0

摘要

高胆红素血症(HB)是新生儿,尤其是早产儿听力损失的一个关键风险因素。在此,我们报告了胆红素(BIL)依赖性细胞死亡在新生小鼠听性脑干(雌雄均有)中的表现,ZD7288(一种超极化激活环核苷酸门控(HCN)通道介导电流(Ih)的阻断剂)或遗传性HCN1缺失可显著减轻这种细胞死亡。GABA 能抑制性中间神经元主要表达 HCN1,BIL 通过增强 HCN1 活性和 Ca2+ 依赖性膜靶向作用,选择性地增加其内在兴奋性和死亡率。在体内对新生小鼠进行慢性 BIL 升高会增加自发活跃中间神经元的比例及其发射频率、Ih 和死亡,从而损害 HCN1+/+ 基因型小鼠在幼年期的听觉,但不会损害 HCN1-/- 基因型小鼠的听觉。我们的结论是,HB 优先靶向 HCN1,伤害抑制性中间神经元,形成一个前馈循环,在这个循环中,抑制作用的减弱会导致过度兴奋、Ca2+ 过载、神经元死亡和听觉障碍。该研究表明,胆红素优先靶向 GABA 能中间神经元,它不仅促进 HCN1 通道的门控,还以钙依赖方式将细胞内 HCN1 靶向质膜,导致神经元过度兴奋、损伤和感觉功能障碍。这些发现表明,HCN1 通道不仅是新生儿胆红素脑病患者听觉异常的潜在驱动因素,也是临床治疗与严重黄疸相关的神经损伤的潜在干预目标。中间神经元对神经毒性的选择性脆弱性可能对理解其他形式的脑损伤具有普遍意义。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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 (I h), 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, I h, 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.

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来源期刊
Journal of Neuroscience
Journal of Neuroscience 医学-神经科学
CiteScore
9.30
自引率
3.80%
发文量
1164
审稿时长
12 months
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
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