Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110, and Department of Psychiatry and Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, Missouri 63110.
J Neurosci. 2014 Mar 26;34(13):4589-98. doi: 10.1523/JNEUROSCI.3451-13.2014.
Metabotropic glutamate receptor 5 (mGluR5) is widely expressed throughout the CNS and participates in regulating neuronal function and synaptic transmission. Recent work in the striatum led to the groundbreaking discovery that intracellular mGluR5 activation drives unique signaling pathways, including upregulation of ERK1/2, Elk-1 (Jong et al., 2009) and Arc (Kumar et al., 2012). To determine whether mGluR5 signals from intracellular membranes of other cell types, such as excitatory pyramidal neurons in the hippocampus, we used dissociated rat CA1 hippocampal cultures and slice preparations to localize and characterize endogenous receptors. As in the striatum, CA1 neurons exhibited an abundance of mGluR5 both on the cell surface and intracellular membranes, including the endoplasmic reticulum and the nucleus where it colocalized with the sodium-dependent excitatory amino acid transporter, EAAT3. Inhibition of EAAT3 or sodium-free buffer conditions prevented accumulations of radiolabeled agonist. Using a pharmacological approach to isolate different pools of mGluR5, both intracellular and cell surface receptors induced oscillatory Ca(2+) responses in dissociated CA1 neurons; however, only intracellular mGluR5 activation triggered sustained high amplitude Ca(2+) rises in dendrites. Consistent with the notion that mGluR5 can signal from intracellular membranes, uncaging glutamate on a CA1 dendrite led to a local Ca(2+) rise, even in the presence of ionotropic and cell surface metabotropic receptor inhibitors. Finally, activation of intracellular mGluR5 alone mediated both electrically induced and chemically induced long-term depression, but not long-term potentiation, in acute hippocampal slices. These data suggest a physiologically relevant and important role for intracellular mGluR5 in hippocampal synaptic plasticity.
代谢型谷氨酸受体 5（mGluR5）广泛表达于中枢神经系统，参与调节神经元功能和突触传递。最近在纹状体中的研究工作带来了突破性的发现，即细胞内 mGluR5 的激活驱动独特的信号通路，包括 ERK1/2、 Elk-1（Jong 等人，2009 年）和 Arc（Kumar 等人，2012 年）的上调。为了确定 mGluR5 是否从细胞内膜（如海马中的兴奋性锥体神经元）发出信号，我们使用分离的大鼠 CA1 海马培养物和切片制备物来定位和表征内源性受体。与纹状体一样，CA1 神经元在细胞表面和细胞内膜上都表现出大量的 mGluR5，包括内质网和核内，在核内它与钠依赖性兴奋性氨基酸转运体 EAAT3 共定位。抑制 EAAT3 或无钠缓冲条件可防止放射性配体的积累。使用药理学方法分离不同池的 mGluR5，细胞内和细胞表面受体都在分离的 CA1 神经元中诱导振荡性 Ca(2+)反应；然而，只有细胞内 mGluR5 的激活才能引发树突中的持续高幅度 Ca(2+)升高。与 mGluR5 可以从细胞内膜发出信号的观点一致，在 CA1 树突上光解谷氨酸会导致局部 Ca(2+)升高，即使存在离子型和细胞表面代谢型受体抑制剂也是如此。最后，单独激活细胞内 mGluR5 介导急性海马切片中的电诱导和化学诱导的长时程抑制，但不介导长时程增强。这些数据表明细胞内 mGluR5 在海马突触可塑性中具有生理相关和重要的作用。
