Department of Anatomy and Neurobiology, Hearing Research Group, College of Medicine, Northeast Ohio Medical University, Rootstown, Ohio 44272.
Department of Biomedical Science, Program in Neuroscience, Florida State University College of Medicine, Tallahassee, Florida 32306.
J Neurosci. 2020 Sep 9;40(37):7027-7042. doi: 10.1523/JNEUROSCI.2771-19.2020. Epub 2020 Aug 12.
One emerging concept in neuroscience states that synaptic vesicles and the molecular machinery underlying spontaneous transmitter release are different from those underlying action potential-driven synchronized transmitter release. Differential neuromodulation of these two distinct release modes by metabotropic glutamate receptors (mGluRs) constitutes critical supporting evidence. However, the mechanisms underlying such a differential modulation are not understood. Here, we investigated the mechanisms of the modulation by group I mGluRs (mGluR Is) on spontaneous glutamate release in the medial nucleus of the trapezoid body (MNTB), an auditory brainstem nucleus critically involved in sound localization. Whole-cell patch recordings from brainstem slices of mice of both sexes were performed. Activation of mGluR I by 3,5-dihydroxyphenylglycine (3,5-DHPG; 200 μm) produced an inward current at -60 mV and increased spontaneous glutamate release in MNTB neurons. Pharmacological evidence indicated involvement of both mGluR1 and mGluR5, which was further supported for mGluR5 by immunolabeling results. The modulation was eliminated by blocking Na channels (tetrodotoxin, 1 μm), persistent Na current (; riluzole, 10 μm), or Ca channels (CdCl, 100 μm). Presynaptic calyx recordings revealed that 3,5-DHPG shifted the activation of to more hyperpolarized voltages and increased at resting membrane potential. Our data indicate that mGluR I enhances spontaneous glutamate release via regulation of and subsequent Ca-dependent processes under resting condition. For brain cells to communicate with each other, neurons release chemical messengers, termed neurotransmitters, in response to action potential invasion (evoked release). Neurons also release neurotransmitters spontaneously. Recent work has revealed different release machineries underlying these two release modes, and their different roles in synaptic development and plasticity. Our recent work discovered differential neuromodulation of these two release modes, but the mechanisms are not well understood. The present study showed that activation of group I metabotropic glutamate receptors enhanced spontaneous glutamate release in an auditory brainstem nucleus, while suppressing evoked release. The modulation is dependent on a persistent Na current and involves subsequent Ca signaling, providing insight into the mechanisms underlying the different release modes in auditory processing.
神经科学的一个新兴概念表明，突触小泡和分子机制基础下的自发递质释放不同于动作电位驱动的同步递质释放。代谢型谷氨酸受体 (mGluR) 对这两种不同释放模式的差异调节构成了关键的支持证据。然而，这种差异调节的机制尚不清楚。在这里，我们研究了 I 组代谢型谷氨酸受体 (mGluR Is) 对内侧梯形核 (MNTB) 中自发谷氨酸释放的调制机制，MNTB 是一个听觉脑干核，在声音定位中起着至关重要的作用。通过两性小鼠脑切片的全细胞膜片钳记录进行研究。用 3,5-二羟基苯甘氨酸 (3,5-DHPG；200 μm) 激活 mGluR I 在 -60 mV 时产生内向电流，并增加 MNTB 神经元的自发谷氨酸释放。药理学证据表明 mGluR1 和 mGluR5 都参与其中，免疫标记结果进一步支持 mGluR5 的参与。该调制被阻断钠通道（河豚毒素，1 μm）、持续钠电流（利鲁唑，10 μm）或钙通道（CdCl，100 μm）所消除。在 presynaptic calyx 记录中发现，3,5-DHPG 将 的激活移向更超极化的电压，并在静息膜电位下增加 。我们的数据表明，mGluR I 通过调节静息状态下的 和随后的 Ca 依赖性过程增强自发谷氨酸释放。为了使脑细胞之间相互交流，神经元在响应动作电位入侵（诱发释放）时释放称为神经递质的化学信使。神经元也会自发释放神经递质。最近的工作揭示了这两种释放模式背后的不同释放机制及其在突触发育和可塑性中的不同作用。我们最近的工作发现了这两种释放模式的差异调节，但机制尚不清楚。本研究表明，I 组代谢型谷氨酸受体的激活增强了听觉脑干核中的自发谷氨酸释放，同时抑制了诱发释放。这种调制依赖于持续的钠电流，并涉及随后的钙信号转导，为听觉处理中不同释放模式的机制提供了深入了解。
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