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_V channels (tetrodotoxin, 1 μm), persistent Na⁺ current (I_NaP; riluzole, 10 μm), or Ca_V channels (CdCl₂, 100 μm). Presynaptic calyx recordings revealed that 3,5-DHPG shifted the activation of I_NaP to more hyperpolarized voltages and increased I_NaP at resting membrane potential. Our data indicate that mGluR I enhances spontaneous glutamate release via regulation of I_NaP and subsequent Ca²⁺-dependent processes under resting condition.

SIGNIFICANCE STATEMENT 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 Ca²⁺ signaling, providing insight into the mechanisms underlying the different release modes in auditory processing.

神经科学中的一个新兴概念指出，突触小泡和自发递质释放的分子机制不同于那些潜在的动作电位驱动的同步递质释放。代谢型谷氨酸受体（mGluRs）对这两种不同的释放模式的差异性神经调节构成了关键的支持证据。但是，尚不了解这种差分调制的基础机制。在这里，我们研究了梯形体（MNTB）的内侧核中的自发谷氨酸释放的第I组mGluRs（mGluR Is）的调节机制，这是一个关键参与声音定位的听觉脑干核。从性别两只老鼠的脑干切片进行全细胞补丁记录。3,5-二羟基苯基甘氨酸激活mGluR I（3，5-DHPG；200微米）在–60 mV处产生内向电流，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均受累，免疫标记结果进一步支持了mGluR5。通过阻断Na _V通道（河豚毒素，1μ米），持续的Na ⁺电流（I _NaP ;利鲁唑_10μ米），或Ca _V通道（CDCL ₂，100μ米）。突触前的花萼录音显示3,5-DHPG将I _NaP的激活转移到更多的超极化电压，并在静息膜电位下增加了I _NaP。我们的数据表明，mGluR I在静息状态下通过调节I _NaP和随后的Ca ²⁺依赖性过程增强自发性谷氨酸的释放。

重要声明为了使脑细胞相互交流，神经元响应动作电位的入侵（诱发的释放）释放化学信使，称为神经递质。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的不同释放机制，以及它们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性神经调节，但其机理尚不清楚。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自发性谷氨酸的释放，同时抑制了诱发的释放。调制取决于持续的Na ⁺电流并涉及随后的Ca²⁺信号传递，可深入了解听觉处理中不同释放模式的潜在机制。