Awad H, Hubert G W, Smith Y, Levey A I, Conn P J
Departments of Pharmacology and Neurology, Graduate Programs in Molecular and Systems Pharmacology and Neuroscience, and Yerkes Regional Primate Research Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
J Neurosci. 2000 Nov 1;20(21):7871-9. doi: 10.1523/JNEUROSCI.20-21-07871.2000.
The subthalamic nucleus (STN) is a key nucleus in the basal ganglia motor circuit that provides the major glutamatergic excitatory input to the basal ganglia output nuclei. The STN plays an important role in normal motor function, as well as in pathological conditions such as Parkinson's disease (PD) and related disorders. Development of a complete understanding of the roles of the STN in motor control and the pathophysiological changes in STN that underlie PD will require a detailed understanding of the mechanisms involved in regulation of excitability of STN neurons. Here, we report that activation of group I metabotropic glutamate receptors (mGluRs) induces a direct excitation of STN neurons that is characterized by depolarization, increased firing frequency, and increased burst-firing activity. In addition, activation of group I mGluRs induces a selective potentiation of NMDA-evoked currents. Immunohistochemical studies at the light and electron microscopic levels indicate that both subtypes of group I mGluRs (mGluR1a and mGluR5) are localized postsynaptically in the dendrites of STN neurons. Interestingly, pharmacological studies suggest that each of the mGluR-mediated effects is attributable to activation of mGluR5, not mGluR1, despite the presence of both subtypes in STN neurons. These results suggest that mGluR5 may play an important role in the net excitatory drive to the STN from glutamatergic afferents. Furthermore, these studies raise the exciting possibility that selective ligands for mGluR5 may provide a novel approach for the treatment of a variety of movement disorders that involve changes in STN activity.
丘脑底核（STN）是基底神经节运动回路中的一个关键核团，它为基底神经节输出核团提供主要的谷氨酸能兴奋性输入。STN在正常运动功能以及帕金森病（PD）等病理状况及相关疾病中发挥着重要作用。要全面了解STN在运动控制中的作用以及PD所基于的STN病理生理变化，就需要详细了解STN神经元兴奋性调节所涉及的机制。在此，我们报告I组代谢型谷氨酸受体（mGluRs）的激活会诱导STN神经元的直接兴奋，其特征为去极化、放电频率增加以及爆发性放电活动增强。此外，I组mGluRs的激活会诱导NMDA诱发电流的选择性增强。光镜和电镜水平的免疫组织化学研究表明，I组mGluRs的两种亚型（mGluR1a和mGluR5）均位于STN神经元树突的突触后部位。有趣的是，药理学研究表明，尽管STN神经元中同时存在两种亚型，但每个mGluR介导的效应均归因于mGluR5的激活，而非mGluR1。这些结果表明，mGluR5可能在谷氨酸能传入神经对STN的净兴奋性驱动中发挥重要作用。此外，这些研究还提出了一个令人兴奋的可能性，即mGluR5的选择性配体可能为治疗涉及STN活动变化的各种运动障碍提供一种新方法。
