Functions of Metabotropic Glutamate Receptor Subtypes

新兴的、临床前、临床和人类遗传学研究提出了一种令人兴奋的可能性，即选择性 代谢型谷氨酸受体(MGlu)的激活剂具有潜在的应用前景 精神分裂症的治疗方法。然而，直到最近，还没有工具可以用来研究 MGlu1在特定大脑回路中的功能作用。我们现在已经开发出高度选择性的mGlu1阳性 变构调节剂(PAM)，以及允许选择性删除特定基因中mGlu1的遗传小鼠系 神经元群。这为确立mGlu1在特定领域中的作用提供了前所未有的机会 精神分裂症患者的大脑回路被破坏。有趣的是，我们最近发现高度选择性 MGlu1 PAM减少纹状体多巴胺(DA)释放并在抗精神病药物啮齿动物模型中具有强大的疗效 活动，如逆转安非他明引起的过度运动活动和感觉运动障碍 门控。根据最近的研究和我们的初步数据，我们假设mGlu1在特定的 也表达d1-DA受体(d1-SPN)的脊髓投射神经元群体负责 MGlu1 PAM抑制DA释放和逆转苯丙胺相关行为效应的能力 用于潜在的抗精神病活性。然而，有可能在DA终末或其他 神经元群体可能负责这些对DA释放的影响以及 MGlu1 PAM。因此，我们将在具体目标1中进行一系列研究，以严格评估 D1-SPN和其他神经细胞中mGlu1在mGlu1 PAM对DA释放和 关联的行为。除了纹状体DA释放的失调外，多项临床和临床前研究 提示GABA能抑制传递在前额叶皮质(PFC)和其他前脑中的丢失 脑区可能在精神分裂症认知缺陷的病理生理变化中起关键作用 病人。此外，在人类和啮齿动物中观察到对NMDA受体阻断的反应是去抑制。 我们现在提供令人兴奋的新的初步数据，表明激活mGlu1可以增加 生长抑素表达抑制中间神经元(SST-INS)和小白蛋白(PV)表达中间神经元(PV-INS) INS)，尤其是SST-INS的兴奋性增强。另外，我们的初步数据 提示PFC中的SST-in对工作记忆至关重要，并使我们假设 SST-ins上的mGlu1可能改善了啮齿动物模型的工作记忆，逆转了工作记忆缺陷。在……里面 具体目标2我们确认了我们初步的电生理学发现，并严格检验了假设 MGlu1的激活通过对SSN-ins的作用增加了抑制信号在PFC的传递。在具体目标3中，我们 将测试SST-INS中mGlu1的激活可以逆转工作记忆和其他 在皮质去抑制的NMDAR功能减退模型中观察到的行为缺陷。这些研究可能 为mGlu1 PAM治疗精神分裂症的治疗潜力提供新的机制见解。

Emerging, preclinical, clinical, and human genetic studies raise the exciting possibility that selective activators of the mGlu1 subtype of metabotropic glutamate (mGlu) receptor have potential utility as a novel approach for treatment for schizophrenia. However, until recently, tools were not available to allow studies of the functional roles of mGlu1 in specific brain circuits. We have now developed highly selective mGlu1 positive allosteric modulators (PAMs), along with genetic mouse lines that allow selective deletion of mGlu1 in specific neuronal populations. This provides an unprecedented opportunity to establish the roles of mGlu1 in specific brain circuits that are disrupted in schizophrenia patients. Interestingly, we recently found that highly selective mGlu1 PAMs reduce striatal dopamine (DA) release and have robust efficacy in rodent models of antipsychotic activity, such as reversal of amphetamine-induced hyper-locomotor activity and disruption of sensory motor gating. Based on recent studies and our preliminary data, we postulate that activation of mGlu1 in a specific population of spinal projection neurons that also express the D1-DA receptor (D1-SPNs) is responsible for the ability of mGlu1 PAMs to inhibit DA release and to reverse behavioral effects of amphetamine that are relevant for potential antipsychotic activity. However, it is possible that activation of mGlu1 in DA terminals or other neuronal populations could be responsible for these effects on DA release and for the behavioral effects of mGlu1 PAMs. Thus, we will perform a series of studies in specific aim 1 to rigorously evaluate the importance of mGlu1 in D1-SPNs and other neuronal populations in the effects of mGlu1 PAMs on DA release and associated behaviors. In addition to dysregulation of striatal DA release, multiple clinical and preclinical studies suggest that loss of GABAergic inhibitory transmission in the prefrontal cortex (PFC) and other forebrain regions may play a critical role in the pathophysiological changes underlying cognitive deficits in schizophrenia patients. Additionally, disinhibition is observed in humans and rodents in response to NMDA receptor blockade. We now present exciting new preliminary data suggesting that activation of mGlu1 can increase activity of somatostatin-expressing inhibitory interneurons (SST-INs) and parvalbumin (PV)-expressing interneurons (PV- INs) in the PFC, with an especially robust increase in excitability of SST-INs. In addition, our preliminary data suggest that SST-INs in the PFC are critical for working memory, and led us to postulate that activation of mGlu1 on SST-INs may improve working memory and reverse working memory deficits in rodent models. In specific aim 2 we confirm our preliminary electrophysiology findings and rigorously test the hypothesis that mGlu1 activation increases inhibitory transmission in the PFC by actions on SSN-INs. In specific aim 3, we will test the hypothesis that activation of mGlu1 in SST-INs can reverse deficits in working memory and other behavioral deficits observed in an NMDAR hypofunction model of cortical disinhibition. These studies could provide new mechanistic insights into the therapeutic potential of mGlu1 PAMs for treatment of schizophrenia.