NAD+ Attenuates Bilirubin-Induced Hyperexcitation in the Ventral Cochlear Nucleus by Inhibiting Excitatory Neurotransmission and Neuronal Excitability.
NAD+ Attenuates Bilirubin-Induced Hyperexcitation in the Ventral Cochlear Nucleus by Inhibiting Excitatory Neurotransmission and Neuronal Excitability.
复制标题
NAD 加通过抑制兴奋性神经传递和神经元兴奋性来减弱胆红素引起的腹侧耳蜗核的过度兴奋
DOI：
10.3389/fncel.2017.00021
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发表时间：
2017
影响因子：
5.3
通讯作者：
Yin SK
中科院分区：
文献类型：
--
作者：
Liang M;Yin XL;Wang LY;Yin WH;Song NY;Shi HB;Li CY;Yin SK
烟酰胺腺嘌呤二核苷酸（NAD+）是一种重要的分子，在多种细胞过程中具有广泛的生物学功能，包括保护细胞免受损伤。然而，关于NAD+在与许多神经退行性病症和疾病相关的神经元兴奋和兴奋性毒性中的作用知之甚少。使用膜片钳记录，我们研究了其对耳蜗腹侧核（VCN），这是特别容易受到胆红素兴奋性毒性的主要神经元的潜在影响。结果发现，NAD+能有效地降低诱发兴奋性突触后电流（eEPSCs）的大小，增加成对脉冲比（PPR），并逆转胆红素对eEPSCs的影响，提示NAD+对突触前释放概率（Pr）有抑制作用。此外，NAD+不仅降低了微型EPSC（mEPSC）的基础频率，而且还逆转了胆红素诱导的mEPSC频率的增加，而不影响其振幅。此外，我们发现，NAD+降低VCN神经元的自发放电频率以及紫红质诱导的放电频率增加。全细胞电流钳记录显示，在突触阻断剂存在下，NAD+可直接降低VCN神经元的内在兴奋性，提示NAD+在突触前和突触后位点均发挥作用。与这些观察结果一致，我们发现由突触前传入神经的高频串刺激触发的第一个突触后锋电位的潜伏期（即，听神经）被NAD+延长。这些结果共同表明，NAD+抑制突触前递质释放和突触后兴奋性，共同削弱兴奋性神经传递。我们的研究结果为探索NAD+预防和治疗胆红素脑病和与其他神经系统疾病相关的兴奋性毒性提供了基础。
Nicotinamide adenine dinucleotide (NAD+) is an important molecule with extensive biological functions in various cellular processes, including protection against cell injuries. However, little is known regarding the roles of NAD+ in neuronal excitation and excitotoxicity associated with many neurodegenerative disorders and diseases. Using patch-clamp recordings, we studied its potential effects on principal neurons in the ventral cochlear nucleus (VCN), which is particularly vulnerable to bilirubin excitotoxicity. We found that NAD+ effectively decreased the size of evoked excitatory postsynaptic currents (eEPSCs), increased paired-pulse ratio (PPR) and reversed the effect of bilirubin on eEPSCs, implicating its inhibitory effects on the presynaptic release probability (Pr). Moreover, NAD+ not only decreased the basal frequency of miniature EPSCs (mEPSCs), but also reversed bilirubin-induced increases in the frequency of mEPSCs without affecting their amplitude under either condition. Furthermore, we found that NAD+ decreased the frequency of spontaneous firing of VCN neurons as well as bilirubin-induced increases in firing frequency. Whole-cell current-clamp recordings showed that NAD+ could directly decrease the intrinsic excitability of VCN neurons in the presence of synaptic blockers, suggesting NAD+ exerts its actions in both presynaptic and postsynaptic loci. Consistent with these observations, we found that the latency of the first postsynaptic spike triggered by high-frequency train stimulation of presynaptic afferents (i.e., the auditory nerve) was prolonged by NAD+. These results collectively indicate that NAD+ suppresses presynaptic transmitter release and postsynaptic excitability, jointly weakening excitatory neurotransmission. Our findings provide a basis for the exploration of NAD+ for the prevention and treatment of bilirubin encephalopathy and excitotoxicity associated with other neurological disorders.