Department of Biological Sciences, University at Buffalo, State University of New York, Buffalo, New York 14260.
Department of Biological Sciences, University at Buffalo, State University of New York, Buffalo, New York 14260
J Neurosci. 2022 Aug 10;42(32):6211-6220. doi: 10.1523/JNEUROSCI.0666-22.2022. Epub 2022 Jul 5.
Exposure to nontraumatic noise drives long-lasting changes in auditory nerve synapses, which may influence hearing, but the induction mechanisms are not known. We mimicked activity in acute slices of the cochlear nucleus from mice of both sexes by treating them with high potassium, after which voltage-clamp recordings from bushy cells indicated that auditory nerve synapses had reduced EPSC amplitude, quantal size, and vesicle release probability ( ). The effects of high potassium were prevented by blockers of nitric oxide (NO) synthase and protein kinase A. Treatment with the NO donor, PAPA-NONOate, also decreased , suggesting NO plays a central role in inducing synaptic changes. To identify the source of NO, we activated auditory nerve fibers specifically using optogenetics. Strobing for 2 h led to decreased EPSC amplitude and , which was prevented by antagonists against ionotropic glutamate receptors and NO synthase. This suggests that the activation of AMPA and NMDA receptors in postsynaptic targets of auditory nerve fibers drives release of NO, which acts retrogradely to cause long-term changes in synaptic function in auditory nerve synapses. This may provide insight into preventing or treating disorders caused by noise exposure. Auditory nerve fibers undergo long-lasting changes in synaptic properties in response to noise exposure , which may contribute to changes in hearing. Here, we investigated the cellular mechanisms underlying induction of synaptic changes using high potassium and optogenetic stimulation and identified important signaling pathways using pharmacology. Our results suggest that auditory nerve activity drives postsynaptic depolarization through AMPA and NMDA receptors, leading to the release of nitric oxide, which acts retrogradely to regulate presynaptic neurotransmitter release. These experiments revealed that auditory nerve synapses are unexpectedly sensitive to activity and can show dramatic, long-lasting changes in a few hours that could affect hearing.
暴露于非创伤性噪声会导致听神经突触发生持久变化，这可能会影响听力，但诱导机制尚不清楚。我们通过用高钾处理雌雄小鼠的耳蜗核急性切片来模拟活性，之后从布什细胞进行电压钳记录表明，听神经突触的 EPSC 幅度、量子大小和囊泡释放概率降低（ ）。一氧化氮（NO）合酶和蛋白激酶 A 的抑制剂可防止高钾引起的作用。用 NO 供体 PAPA-NONOate 处理也降低了 ，表明 NO 在诱导突触变化中起核心作用。为了确定 NO 的来源，我们使用光遗传学特异性激活听神经纤维。2 小时的频闪导致 EPSC 幅度和 的降低，该降低可被针对离子型谷氨酸受体和 NO 合酶的拮抗剂所预防。这表明，听神经纤维在其 Postsynaptic 靶点中的 AMPA 和 NMDA 受体的激活驱动了 NO 的释放，NO 逆行作用导致听神经突触中突触功能的长期变化。这可能为预防或治疗噪声暴露引起的疾病提供思路。听觉神经纤维在突触特性上会发生持久变化以响应噪声暴露，这可能导致听力变化。在这里，我们使用高钾和光遗传学刺激研究了诱导突触变化的细胞机制，并使用药理学确定了重要的信号通路。我们的结果表明，听觉神经活性通过 AMPA 和 NMDA 受体驱动 Postsynaptic 去极化，导致一氧化氮的释放，一氧化氮逆行作用调节 Presynaptic 神经递质释放。这些实验表明，听觉神经突触对活性异常敏感，在数小时内即可显示出明显的、持久的变化，从而影响听力。
