Optopharmacological studies of presynaptic metabotropic glutamate receptor 2 in corticolimbic circuits

皮质边缘回路突触前代谢型谷氨酸受体 2 的光药理学研究

• 批准号: 10241285
• 负责人: Vanessa Gutzeit
• 金额: $ 1.85万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2021-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241285
• 关键词: Address; Affect; Amygdaloid structure; Anxiety; Anxiety Disorders; Area; Autoreceptors; Behavior; Behavior Control; Behavioral; Behavioral Symptoms; Binding; Brain; Brain region; Chronic; Chronic stress; Clinical Research; Clinical Trials; Cognition; Cognitive; Cognitive deficits; Coupled; Disease; Dissection; Dopaminergic Agents; Electrophysiology (science); Environment; Equilibrium; Fright; Functional disorder; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genetic; Glutamate Receptor; Glutamates; Homeostasis; Human; Impaired cognition; Ion Channel; Ligands; Link; Medial; Mediating; Mediator of activation protein; Mental Depression; Mental disorders; Metabotropic Glutamate Receptors; Methods; Molecular; Mood Disorders; Moods; Mus; Nervous System Physiology; Neurologic; Neurons; Neurotransmitters; Optics; Patients; Pharmacology; Phenotype; Play; Population; Prefrontal Cortex; Psychiatric therapeutic procedure; Receptor Activation; Regulation; Research; Rewards; Rodent; Rodent Model; Role; Serotonin Agents; Signal Transduction; Stress; Symptoms; Synapses; System; Techniques; Testing; Up-Regulation; Viral; anxiety symptoms; associated symptom; awake; behavioral phenotyping; cell type; design; experimental study; glutamatergic signaling; in vivo; insight; metabotropic glutamate receptor 2; metabotropic glutamate receptor 3; mood regulation; neurophysiology; neuroregulation; new therapeutic target; next generation; novel; optogenetics; photoactivation; preclinical study; preclinical trial; presynaptic; receptor; reduce symptoms; social defeat; spatiotemporal; synaptic function

ABSTRACT Psychiatric disorders are extremely common throughout the human population and remain among the most expensive and difficult illnesses to treat. Psychiatric disorders consist of many types of conditions, including forms of anxiety and depression, which have many overlapping symptoms, including cognitive deficits. In order to identify new drug targets to treat these disorders, research has shifted beyond serotonergic and dopaminergic drugs, and has recently focused on targeting the glutamatergic system in the brain. Glutamate is the most abundant neurotransmitter in the brain, and plays a critical role in maintaining neurological homeostasis. A major cause of psychiatric disorders is stress, which can affect glutamatergic signaling in numerous ways. For these reasons, glutamate receptors are being evaluated as mediators of disease pathophysiology and as potential treatment targets. Specifically, metabotropic glutamate receptors (mGluRs) are G protein-coupled recepetors (GPCRs) which play a neuromodulatory role in sensing and regulating glutamate release at the synapse. Preclinical and clinical trials targeting mGluR2 and mGluR3, inhibitory Gi/o-coupled mGluRs, have shown some promise in reducing anxiety. However, other trials have failed or had mixed results, indicating that a more precise dissection of the role of mGluRs in the neurophysiology of psychiatric disorders is needed. mGluR2 is a unique target at glutamate synapses due to its predominant expression as a presynaptic autoreceptor, where it inhibits glutamate release and, following prolonged activation, can causes long-term changes in synaptic strength. Importantly, mGluR2 is highly expressed in the medial prefrontal cortex (mPFC) and the basolatoral amygdala (BLA), key regions that regulate both mood and cognition. Disruption in the mPFC-BLA corticolimbic circuit plays a key role in psychiatric disorders, and many human studies indicate connectivity between these brain regions is disrupted in psychiatric patients. Some studies indicate that mGluR2 plays a critical role in regulating neuronal activity in the mPFC and BLA, but the underlying mechanisms are unclear. Current pharmacological methods cannot distinguish between mGluR2 and mGluR3, and do not provide spatial, temporal, or cell type-specific targeting in order to elucidate the function of specific mGluR2 sub-populations in the brain. This proposal aims to use new optogenetic techniques to address current gaps in the understanding of the expression, signaling, and behavioral changes elicited by presynaptic mGluR2 within the mPFC–BLA circuit in a stress-induced rodent model of mood disorders.

抽象的 精神疾病在整个人口中极为普遍，并且仍然存在 在治疗最昂贵，最困难的疾病中。精神疾病由许多人组成 条件类型，包括动画和抑郁的形式，这些形式有许多重叠 症状，包括认知缺陷。为了识别新药物的治疗 疾病，研究已经超越了血清素能和多巴胺能药物，最近已有 专注于靶向大脑中的谷氨酸能系统。谷氨酸是最丰富的 大脑中的神经递质，在维持神经系统稳态中起着至关重要的作用。一个 精神疾病的主要原因是压力，这可能会影响谷氨酸能信号传导 多种方式。由于这些原因，正在评估谷氨酸受体 疾病病理生理学和作为潜在治疗靶标。具体而言，代谢性 谷氨酸受体（MGLURS）是G蛋白偶联受体（GPCR） 神经调节作用在敏感性和调节突触处的谷氨酸释放。临床前和 针对MGLUR2和MGLUR3的临床试验，抑制性GI/O耦合mglurs已显示一些 有望减轻焦虑。但是，其他试验失败或结果不同，表明 mglurs在精神病学神经生理学中的作用的更精确的解剖 需要疾病。 Mglur2是谷氨酸突触的独特目标 表达作为突触前自身受体，它抑制谷氨酸释放并随后 长时间的激活会导致突触强度的长期变化。重要的是，mglur2是 在介质前额叶皮层（MPFC）和副杏仁核（BLA）中高度表达 调节情绪和认知的关键区域。 MPFC-Bla Corticolimbic中断 电路在精神疾病中起关键作用，许多人类研究表明连通性 在这些大脑区域之间，精神病患者中断。一些研究表明 MGLUR2在调节MPFC和BLA的神经元活性中起着至关重要的作用，但是 基本机制尚不清楚。当前的药物方法无法区分 在MGLUR2和MGLUR3之间，并且不提供空间，临时或细胞类型的靶向 为了阐明大脑中特定的MGLUR2亚群的功能。这个建议 旨在使用新的光遗传技术来解决当前差距 突触前MGLUR2引起的表达，信号传导和行为变化 在应力引起的情绪障碍啮齿动物模型中的MPFC – BLA电路。

项目成果

A fine-tuned azobenzene for enhanced photopharmacology in vivo.

• DOI: 10.1016/j.chembiol.2021.02.020
• 发表时间: 2021-11-18
• 期刊: Cell chemical biology
• 影响因子: 8.6
• 作者: Gutzeit VA;Acosta-Ruiz A;Munguba H;Häfner S;Landra-Willm A;Mathes B;Mony J;Yarotski D;Börjesson K;Liston C;Sandoz G;Levitz J;Broichhagen J
• 通讯作者: Broichhagen J