Pittsburgh Hearing Research Center and Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261.
Department of Chemistry, Colgate University, Hamilton, New York 13346.
J Neurosci. 2020 Jun 24;40(26):4981-4996. doi: 10.1523/JNEUROSCI.0175-20.2020. Epub 2020 May 20.
In many brain areas, such as the neocortex, limbic structures, and auditory brainstem, synaptic zinc is released from presynaptic terminals to modulate neurotransmission. As such, synaptic zinc signaling modulates sensory processing and enhances acuity for discrimination of different sensory stimuli. Whereas sensory experience causes long-term changes in synaptic zinc signaling, the mechanisms underlying this long-term synaptic zinc plasticity remain unknown. To study these mechanisms in male and female mice, we used and models of zinc plasticity observed at the zinc-rich glutamatergic dorsal cochlear nucleus (DCN) parallel fiber synapses onto cartwheel cells. High-frequency stimulation of DCN parallel fiber synapses induced LTD of synaptic zinc signaling (Z-LTD), evidenced by reduced zinc-mediated inhibition of EPSCs. Low-frequency stimulation induced LTP of synaptic zinc signaling (Z-LTP), evidenced by enhanced zinc-mediated inhibition of EPSCs. Pharmacological manipulations of Group 1 metabotropic glutamate receptors (G1 mGluRs) demonstrated that G1 mGluR activation is necessary and sufficient for inducing Z-LTD and Z-LTP. Pharmacological manipulations of Ca dynamics indicated that rises in postsynaptic Ca are necessary and sufficient for Z-LTD induction. Electrophysiological measurements assessing postsynaptic expression mechanisms, and imaging studies with a ratiometric extracellular zinc sensor probing zinc release, supported that Z-LTD is expressed, at least in part, via reductions in presynaptic zinc release. Finally, exposure of mice to loud sound caused G1 mGluR-dependent Z-LTD at DCN parallel fiber synapses, thus validating our results. Together, our results reveal a novel mechanism underlying activity- and experience-dependent plasticity of synaptic zinc signaling. In the neocortex, limbic structures, and auditory brainstem, glutamatergic nerve terminals corelease zinc to modulate excitatory neurotransmission and sensory responses. Moreover, sensory experience causes bidirectional, long-term changes in synaptic zinc signaling. However, the mechanisms of this long-term synaptic zinc plasticity remain unknown. Here, we identified a novel Group 1 mGluR-dependent mechanism that causes bidirectional, long-term changes in synaptic zinc signaling. Our results highlight new mechanisms of brain adaptation during sensory processing, and potentially point to mechanisms of disorders associated with pathologic adaptation, such as tinnitus.
在许多脑区，如新皮层、边缘结构和听觉脑干，突触锌从突触前末梢释放出来，调节神经递质传递。因此，突触锌信号调节感觉处理，并增强对不同感觉刺激的辨别能力。尽管感觉经验会导致突触锌信号的长期变化，但这种长期突触锌可塑性的机制尚不清楚。为了研究雄性和雌性小鼠中的这些机制，我们使用了在富含锌的谷氨酸能耳蜗核（DCN）平行纤维突触到车轮细胞上观察到的锌可塑性的 和 模型。DCN 平行纤维突触的高频刺激诱导了突触锌信号的 LTD（Z-LTD），表现为锌介导的 EPSC 抑制减少。低频刺激诱导了突触锌信号的 LTP（Z-LTP），表现为锌介导的 EPSC 抑制增强。I 组代谢型谷氨酸受体（G1 mGluR）的药理学操作表明，G1 mGluR 的激活对于诱导 Z-LTD 和 Z-LTP 是必要和充分的。钙动力学的药理学操作表明，突触后 Ca 的升高对于 Z-LTD 的诱导是必要和充分的。评估突触后表达机制的电生理学测量和使用比率型细胞外锌传感器探测锌释放的成像研究支持 Z-LTD 的表达，至少部分是通过减少突触前锌释放来实现的。最后，将小鼠暴露于强声会导致 DCN 平行纤维突触处 G1 mGluR 依赖性 Z-LTD，从而验证了我们的 结果。总之，我们的结果揭示了突触锌信号活性和经验依赖性可塑性的一种新机制。在新皮层、边缘结构和听觉脑干中，谷氨酸能神经末梢共同释放锌来调节兴奋性神经递质传递和感觉反应。此外，感觉经验会导致突触锌信号的双向、长期变化。然而，这种长期突触锌可塑性的机制尚不清楚。在这里，我们发现了一种新的 G1 mGluR 依赖性机制，它导致了突触锌信号的双向、长期变化。我们的研究结果突出了在感觉处理过程中大脑适应的新机制，并可能为与病理性适应相关的疾病的机制提供线索，如耳鸣。
