Optopharmacological studies of presynaptic metabotropic glutamate receptor 2 in corticolimbic circuits

摘要 精神障碍在整个人类群体中极为常见，并且仍然存在。 精神疾病是最昂贵和最难治疗的疾病之一。精神疾病包括许多 类型的条件，包括形式的焦虑和抑郁，其中有许多重叠 症状，包括认知缺陷。为了确定新的药物靶点来治疗这些 研究已经超越了多巴胺能和多巴胺能药物，最近 专注于针对大脑中的多巴胺能系统。谷氨酸是最丰富的 它是大脑中的神经递质，在维持神经稳态中起着关键作用。一 精神疾病的主要原因是压力，压力会影响大脑中的谷氨酸能信号传导 很多种方式。由于这些原因，谷氨酸受体被评估为 疾病病理生理学和作为潜在的治疗靶点。具体来说，代谢型 谷氨酸受体（mGluRs）是G蛋白偶联受体（GPCR）， 在突触处的谷氨酸释放的感觉和调节中的神经调节作用。临床前和 靶向mGluR 2和mGluR 3（抑制性Gi/o偶联mGluR）的临床试验已经显示出一些 承诺减少焦虑。然而，其他试验失败或结果好坏参半，表明 对mGluRs在精神疾病神经生理学中的作用进行了更精确的分析， 失调是需要的。mGluR 2是谷氨酸突触的独特靶点，这是由于其主要的 作为突触前自身受体表达，在那里它抑制谷氨酸释放， 延长激活时间，会导致突触强度的长期变化。重要的是，mGluR 2是 在内侧前额叶皮层（mPFC）和基底杏仁核（BLA）中高度表达， 调节情绪和认知的关键区域。mPFC-BLA皮质边缘的破坏 回路在精神疾病中起着关键作用，许多人类研究表明， 在精神病患者中这些脑区之间的联系被破坏了。一些研究表明 mGluR 2在调节mPFC和BLA中的神经元活动中起关键作用，但是， 潜在的机制尚不清楚。目前的药理学方法无法区分 在mGluR 2和mGluR 3之间，并且不提供空间、时间或细胞类型特异性靶向 以阐明脑中特定mGluR 2亚群的功能。这项建议 旨在使用新的光遗传学技术来解决目前在理解 突触前mGluR 2引起的表达、信号传导和行为变化， mPFC-BLA回路在应激诱导的啮齿动物模型的情绪障碍。

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.