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首页> 外文期刊>Toxicology Letters: An International Journal Providing a Forum for Original and Pertinent Contributions in Toxicology Research >The role of gamma-aminobutyric acid/glycinergic synaptic transmission in mediating bilirubin-induced hyperexcitation in developing auditory neurons
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The role of gamma-aminobutyric acid/glycinergic synaptic transmission in mediating bilirubin-induced hyperexcitation in developing auditory neurons

机译：γ-氨基丁酸/甘氨酸能突触传递在介导胆红素诱导的过度兴奋发展听觉神经元中的作用

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摘要

Hyperbilirubinemia is a common clinical phenomenon observed in human newborns. A high level of bilirubin can result in severe jaundice and bilirubin encephalopathy. However, the cellular mechanisms underlying bilirubin excitotoxicity are unclear. Our previous studies showed the action of gamma-aminobutyric acid (GABA)/glycine switches from excitatory to inhibitory during development in the ventral cochlear nucleus (VCN), one of the most sensitive auditory nuclei to bilirubin toxicity. In the present study, we investigated the roles of GABA(A)/glycine receptors in the induction of bilirubin hyperexcitation in early developing neurons. Using the patch clamp technique, GABA(A)/glycine receptor-mediated spontaneous inhibitory synaptic currents (sIPSCs) were recorded from bushy and stellate cells in acute brainstem slices from young mice (postnatal day 2-6). Bilirubin significantly increased the frequency of sIPSCs, and this effect was prevented by pretreatments of slices with either fast or slow Ca2+ chelators BAPTA-AM and EGTA-AM suggesting that bilirubin can increase the release of GABA/glycine via Ca2+-dependent mechanisms. Using cell-attached recording configuration, we found that antagonists of GABA(A) and glycine receptors strongly attenuated spontaneous spiking firings in P2-6 neurons but produced opposite effect in P15-19 neurons. Furthermore, these antagonists reversed bilirubin-evoked hyperexcitability in P2-6 neurons, indicating that excitatory action of GABA/glycinergic transmission specifically contribute to bilirubin-induced hyperexcitability in the early stage of development. Our results suggest that bilirubin-induced enhancement of presynaptic release GABA/Glycine via Ca2+-dependent mechanisms may play a critical role in mediating neuronal hyperexcitation associated with jaundice, implicating potential new strategies for predicting, preventing, and treating bilirubin neurotoxicity. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
机译：高胆红素血症是在人类新生儿中观察到的常见临床现象。高水平的胆红素可导致严重的黄疸和胆红素脑病。但是，尚不清楚胆红素兴奋性毒性的细胞机制。我们以前的研究表明，在对胆红素毒性最敏感的听觉核之一的腹侧耳蜗核（VCN）发育过程中，γ-氨基丁酸（GABA）/甘氨酸的作用从兴奋性转变为抑制性。在本研究中，我们调查了GABA（A）/甘氨酸受体在早期发育神经元中诱导胆红素过度兴奋中的作用。使用膜片钳技术，在幼鼠的急性脑干切片中（出生后第2-6天）从浓密和星状细胞中记录了GABA（A）/甘氨酸受体介导的自发抑制突触电流（sIPSC）。胆红素显着增加了sIPSC的频率，而用快或慢Ca2 +螯合剂BAPTA-AM和EGTA-AM预处理切片可防止这种作用，这表明胆红素可通过Ca2 +依赖性机制增加GABA /甘氨酸的释放。使用细胞附着的记录配置，我们发现GABA（A）和甘氨酸受体的拮抗剂强烈减弱了P2-6神经元的自发尖峰放电，但在P15-19神经元中产生了相反的作用。此外，这些拮抗剂逆转了P2-6神经元中胆红素引起的过度兴奋性，表明GABA /甘氨酸能传递的兴奋作用在发育的早期特别有助于胆红素诱导的过度兴奋性。我们的结果表明，胆红素诱导的通过Ca2 +依赖性机制的突触前释放GABA /甘氨酸增强可能在介导与黄疸相关的神经元过度兴奋中起关键作用，暗示了预测，预防和治疗胆红素神经毒性的潜在新策略。 （C）2015 Elsevier Ireland Ltd.保留所有权利。

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