PDF(Pubmed)
Abstract：
Metabotropic glutamate receptor 8 (mGlu8) is a heterogeneously expressed and poorly understood glutamate receptor with potential pharmacological significance. The thalamic reticular nucleus (TRN) is a critical inhibitory modulator of the thalamocortical-corticothalamic (TC-CT) network and plays a crucial role in information processing throughout the brain, is implicated in a variety of psychiatric conditions, and is also a site of significant mGlu8 expression. Using both male and female mice, we determined via fluorescent in situ hybridization that parvalbumin-expressing cells in the TRN core and shell matrices (identified by spp1+ and ecel1+ expression, respectively), as well as the cortical layers involved in CT signaling, express grm8 mRNA. We then assayed the physiological and behavioral impacts of perturbing grm8 signaling in the TC circuit through conditional (adeno-associated virus-CRE mediated) and cell-type-specific constitutive deletion strategies. We show that constitutive parvalbumin grm8 knock-out (PV grm8 knock-out) mice exhibited (1) increased spontaneous excitatory drive onto dorsal thalamus relay cells and (2) impaired sensorimotor gating, measured via paired-pulse inhibition, but observed no differences in locomotion and thigmotaxis in repeated bouts of open field test (OFT). Conversely, we observed hyperlocomotive phenotypes and anxiolytic effects of AAV-mediated conditional knockdown of grm8 in the TRN (TRN grm8 knockdown) in repeated OFT. Our findings underscore a role for mGlu8 in regulating excitatory neurotransmission as well as anxiety-related locomotor behavior and sensorimotor gating, revealing potential therapeutic applications for various neuropsychiatric disorders and guiding future research endeavors into mGlu8 signaling and TRN function.
摘要：
代谢型谷氨酸受体8（mGlu8）是一种异质表达且鲜为人知的谷氨酸受体，具有潜在的药理学意义。丘脑网状核（TRN）是丘脑皮质-皮质丘脑（TC-CT）网络的关键抑制调节剂，在整个大脑的信息处理中起着至关重要的作用。与各种精神疾病有关，并且也是显著的mGlu8表达的位点。使用雄性和雌性小鼠，我们通过荧光原位杂交确定了TRN核心和外壳基质中表达小清蛋白的细胞（通过spp1和ecel1表达鉴定，分别）以及参与皮质丘脑信号传导的皮质层，表达grm8mRNA。然后，我们通过条件（AAV-CRE介导的）和细胞类型特异性组成型缺失策略，分析了TC电路中扰动grm8信号的生理和行为影响。我们表明，组成型小白蛋白grm8敲除（PVgrm8KO）小鼠表现出1）增加的对背侧丘脑中继细胞的自发兴奋性驱动和2）受损的感觉运动门控，通过成对脉冲抑制测量，但是在重复的野外测试中，运动和thigmotaxis没有差异。相反，在重复的开放场测试中，我们观察到了AAV介导的有条件敲除TRN（TRNgrm8KD）中grm8的高机车表型和抗焦虑作用。我们的发现强调了mGlu8在调节兴奋性神经传递以及焦虑相关的运动行为和感觉运动门控中的作用，揭示各种神经精神疾病的潜在治疗应用，并指导未来mGlu8信号传导和TRN功能的研究工作。意义陈述III组mGlu受体和丘脑网状核（TRN）是皮质丘脑相互神经传递的关键调节剂，与焦虑和运动行为有关。本研究表明，TRN和丘脑投射皮质层中grm8mRNA的特异性富集，并表征了mGlu8受体在控制自发兴奋性神经传递到位于背侧丘脑内的细胞上以及调节开放视野和PPI测试的感觉运动行为中的作用。这些发现增加了有关TRN和grm8调节丘脑皮质活动以及与神经和神经精神疾病有关的相关行为的文献。
