Functions of Metabotropic Glutamate Receptor Subtypes

代谢型谷氨酸受体亚型的功能

• 批准号: 10205709
• 负责人: P Jeffrey Conn
• 金额: $ 48.45万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10205709
• 关键词: Address; Amphetamines; Antipsychotic Agents; Behavior; Behavioral; Biosensor; Brain; CNR2 gene; Cells; Clinical Research; Cognitive deficits; Corpus striatum structure; Data; Delusions; Disease; Disinhibition; Dopamine; Dopamine D1 Receptor; Electrophysiology (science); Endocannabinoids; Fiber; GRM1 gene; Genes; Genetic; Genetic study; Hallucinations; Human; Human Genetics; Impaired cognition; Interneurons; Knockout Mice; Mediating; Medical Genetics; Memory impairment; Metabotropic Glutamate Receptors; Modeling; Modernization; Motor; Motor Activity; Mus; Muscarinic Acetylcholine Receptor; N-Methyl-D-Aspartate Receptors; Neurons; Parvalbumins; Pathologic; Patients; Periodicity; Photometry; Play; Population; Prefrontal Cortex; Prosencephalon; Pyramidal Cells; Rodent; Rodent Model; Role; Scanning; Schizophrenia; Sensory; Series; Short-Term Memory; Signal Transduction; Single Nucleotide Polymorphism; Somatostatin; Spinal; Symptoms; Testing; Therapeutic; Viral; Whole-Cell Recordings; associated symptom; base; behavioral response; cannabinoid receptor; cell type; dopaminergic neuron; genome wide association study; improved; insight; loss of function; novel; novel strategies; optogenetics; positive allosteric modulator; pre-clinical; preclinical study; response; selective expression; synaptic inhibition; tool; transmission process

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.

新兴的，临床前，临床和人类遗传学研究提出了令人兴奋的可能性，选择性 代谢型谷氨酸（mGlu）受体的mGlu 1亚型的激活剂具有作为新的代谢型谷氨酸受体的潜在用途， 精神分裂症的治疗方法。然而，直到最近，还没有工具来研究 mGlu 1在特定脑回路中的功能作用。我们现在已经开发出高选择性mGlu 1阳性 变构调节剂（PAM），沿着遗传小鼠品系，其允许选择性缺失特异性表达的mGlu 1， 神经元群体。这提供了一个前所未有的机会，以确定mGlu 1在特定的细胞中的作用。 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， mGlu 1 PAM减少纹状体多巴胺（DA）释放，并在抗精神病药物的啮齿动物模型中具有稳健的疗效 活动，如安非他明诱导的过度运动活动和感觉运动中断的逆转 门控基于最近的研究和我们的初步数据，我们假设在一个特定的细胞中激活mGlu 1， 也表达D1-DA受体（D1-SPNs）的脊髓投射神经元群体负责 mGlu 1 PAM抑制DA释放和逆转安非他明行为效应的能力， 潜在的抗精神病活性然而，在DA终末或其他神经元中激活mGlu 1可能是一个潜在的原因。 神经元群体可能是负责这些影响DA释放和行为的影响， 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和其他神经元群体中mGlu 1对mGlu 1 PAM对DA释放的影响， 相关的行为。除了纹状体DA释放的失调外，多项临床和临床前研究 表明前额叶皮层（PFC）和其它前脑中GABA能抑制性传递丧失 区域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 患者此外，在人类和啮齿类动物中观察到对NMDA受体阻断的响应的去抑制。 我们现在提出了令人兴奋的新的初步数据，表明激活mGlu 1可以增加 表达生长抑素的抑制性中间神经元（SST-INs）和表达小白蛋白（PV-）的中间神经元（PV- INs）在PFC中，特别是在SST-INs的兴奋性增加。此外，我们的初步数据 这表明前额叶皮层中的SST-IN对工作记忆至关重要，并使我们假设 SST-IN上的mGlu 1可以改善啮齿动物模型中的工作记忆并逆转工作记忆缺陷。在 具体目标2我们证实了我们初步的电生理学发现，并严格检验了以下假设： mGlu 1激活通过作用于SSN-IN增加PFC中的抑制性传递。 将检验这一假设，即在SST-IN中激活mGlu 1可以逆转工作记忆和其他功能的缺陷。 在皮层去抑制的NMDAR功能减退模型中观察到的行为缺陷。这些研究可以 为mGlu 1 PAM治疗精神分裂症的治疗潜力提供了新的机制见解。