Department of Pharmacology, Vanderbilt University, Nashville, TN, 37232, USA.
Vanderbilt Center for Neuroscience Drug Discovery, Nashville, TN, 37232, USA.
Mol Psychiatry. 2019 Jun;24(6):916-927. doi: 10.1038/s41380-017-0015-z. Epub 2017 Dec 21.
Stress can precipitate or worsen symptoms of many psychiatric disorders by dysregulating glutamatergic function within the prefrontal cortex (PFC). Previous studies suggest that antagonists of group II metabotropic glutamate (mGlu) receptors (mGlu and mGlu) reduce stress-induced anhedonia through actions in the PFC, but the mechanisms by which these receptors act are not known. We now report that activation of mGlu induces long-term depression (LTD) of excitatory transmission in the PFC at inputs from the basolateral amygdala. Our data suggest mGlu-LTD is mediated by postsynaptic AMPAR internalization in PFC pyramidal cells, and we observed a profound impairment in mGlu-LTD following a single, 20-min restraint stress exposure. Finally, blocking mGlu activation in vivo prevented the stress-induced maladaptive changes to amydalo-cortical physiology and motivated behavior. These data demonstrate that mGlu mediates stress-induced physiological and behavioral impairments and further support the potential for mGlu modulation as a treatment for stress-related psychiatric disorders.
压力通过调节前额叶皮层（PFC）中的谷氨酸能功能，可引发或加重许多精神疾病的症状。先前的研究表明，代谢型谷氨酸受体（mGlu 和 mGlu）的 II 组拮抗剂通过 PFC 中的作用减少应激引起的快感缺失，但这些受体的作用机制尚不清楚。我们现在报告，mGlu 的激活可诱导来自外侧杏仁核的 PFC 中的兴奋性传递的长时程抑制（LTD）。我们的数据表明，mGlu-LTD 是由 PFC 锥体细胞中的突触后 AMPAR 内吞介导的，并且我们在单次 20 分钟的束缚应激暴露后观察到 mGlu-LTD 明显受损。最后，体内阻断 mGlu 的激活可防止应激引起的杏仁皮质生理和动机行为的适应性变化。这些数据表明 mGlu 介导应激引起的生理和行为障碍，进一步支持 mGlu 调节作为治疗与应激相关的精神疾病的潜力。
