Neurotransmitter- and Release-Mode-Specific Modulation of Inhibitory Transmission by Group I Metabotropic Glutamate Receptors in Central Auditory Neurons of the Mouse
Neurotransmitter- and Release-Mode-Specific Modulation of Inhibitory Transmission by Group I Metabotropic Glutamate Receptors in Central Auditory Neurons of the Mouse
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DOI：
10.1523/jneurosci.0603-18.2018
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发表时间：
2018-09-19
影响因子：
5.3
通讯作者：
Lu, Yong
中科院分区：
文献类型：
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作者：
Curry, Rebecca J.;Peng, Kang;Lu, Yong
由代谢型谷氨酸受体（mGluRs）介导的神经调节调节许多脑功能。然而，在正常和疾病状态下的听觉系统中的mGluRs的功能还没有得到很好的理解。斜方体内侧核（MNTB）是脑干听觉核团中参与声音定位的重要核团。除了经典的花萼兴奋性输入外，MNTB神经元还接受突触抑制，并且仍然完全不知道这种抑制是如何调节的。在这里，使用全细胞电压钳在脑切片中，我们研究了组I mGluR（mGluR I）介导的调制甘氨酸能和GABA能输入到MNTB神经元在WT小鼠和脆性X综合征（FXS）小鼠模型（两种性别），其中脆性X智力低下基因1被敲除（Fmr 1 KO），导致夸张的活动mGluR I和行为表型。通过（RS）-3，5-二羟基苯甘氨酸（3，5-DHPG）激活mGluR I以电压门控钠通道依赖性方式增加WT和Fmr 1 KO神经元中甘氨酸能自发IPSC（sIPSC）的频率和振幅，但不调节甘氨酸能诱发的IPSC（eIPSC）。相反，3，5-DHPG不影响GABA能sIPSC，但通过内源性大麻素信号传导抑制WT神经元中的eIPSC。在KO中，3，5-DHPG对GABA能eIPSC的作用是高度可变的，这支持FXS模型中受损的GABA能信号传导的概念。sIPSC和eIPSC的差异调节以及甘氨酸能和GABA能传递的差异调节表明了负责抑制性递质的自发和诱发释放及其通过mGluR I信号传导途径的调节的不同机制。
Neuromodulation mediated by metabotropic glutamate receptors (mGluRs) regulates many brain functions. However, the functions of mGluRs in the auditory system under normal and diseased states are not well understood. The medial nucleus of the trapezoid body (MNTB) is a critical nucleus in the auditory brainstem nuclei involved in sound localization. In addition to the classical calyx excitatory inputs, MNTB neurons also receive synaptic inhibition and it remains entirely unknown how this inhibition is regulated. Here, using whole-cell voltage clamp in brain slices, we investigated group I mGluR (mGluR I)-mediated modulation of the glycinergic and GABAergic inputs to MNTB neurons in both WT mice and a fragile X syndrome (FXS) mouse model (both sexes) in which the fragile X mental retardation gene 1 is knocked out (Fmr1 KO), causing exaggerated activity of mGluR I and behavioral phenotypes. Activation of mGluR I by (RS)-3,5-dihydroxyphenylglycine (3,5-DHPG) increased the frequency and amplitude of glycinergic spontaneous IPSCs (sIPSCs) in both WT and Fmr1 KO neurons in a voltage-gated sodium channel-dependent fashion, but did not modulate glycinergic evoked IPSCs (eIPSCs). In contrast, 3,5-DHPG did not affect GABAergic sIPSCs, but did suppress eIPSCs in WT neurons via endocannabinoid signaling. In the KO, the effect of 3,5-DHPG on GABAergic eIPSCs was highly variable, which supports the notion of impaired GABAergic signaling in the FXS model. The differential modulation of sIPSC and eIPSC and differential modulation of glycinergic and GABAergic transmission suggest distinct mechanisms responsible for spontaneous and evoked release of inhibitory transmitters and their modulation through the mGluR I signaling pathway.