Role of Phospholipase D in M1 Allosteric Modulation of Synaptic Plasticity: Implications for the Treatment of Schizophrenia

磷脂酶 D 在突触可塑性 M1 变构调节中的作用：对精神分裂症治疗的影响

• 批准号: 9393416
• 负责人: Sean Patrick Moran
• 金额: $ 2.87万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9393416
• 关键词: Adolescent Development; Adverse effects; Affect; Agonist; Anhedonia; Animals; Antipsychotic Agents; Behavioral; Biochemistry; Biology; Brain; Calcium; Chemosensitization; Cognition; Cognitive; Communication; Coupling; Data; Electrophysiology (science); Functional disorder; Genetic; Impaired cognition; Impairment; Individual; Knockout Mice; Lead; Learning; Light; Long-Term Depression; Medial; Mediating; Memory; Modeling; Mus; Muscarinic Acetylcholine Receptor; Muscarinic M1 Receptor; N-Methyl-D-Aspartate Receptors; NR1 NMDA receptor; Neurobehavioral Manifestations; Patients; Peripheral; Pharmacology; Phospholipase C; Phospholipase D; Play; Prefrontal Cortex; Property; Protein Isoforms; Protein Kinase C; Reporting; Research Proposals; Rodent Model; Role; Schizophrenia; Series; Signal Pathway; Signal Transduction; Slice; Social Interaction; Stimulus; Symptoms; Synapses; Synaptic plasticity; Testing; Therapeutic; Therapeutic Agents; Work; behavioral response; clinical development; cognitive enhancement; cognitive function; improved; in vivo; inhibitor/antagonist; insight; interest; knock-down; member; new therapeutic target; novel; positive allosteric modulator; protein activation; receptor; response; tool

Project Summary Agents that activate muscarinic acetylcholine receptors (mAChRs) have exciting potential as novel treatments for the negative symptoms and cognitive disturbances in patients suffering from schizophrenia. Previous mAChR agonists failed in clinical development due to a lack of selectivity for individual mAChR subtypes and adverse effects associated with activation of peripheral mAChRs. We have now discovered and characterized highly selective positive allosteric modulators (PAMs) for individual mAChR subtypes and found that selective PAMs for the M1 mAChR have robust cognition-enhancing effects and may have actions that predict reduction in negative symptoms. Of specific interest was the finding that M1 PAMs enhance a form of M1-dependent long-term depression, termed mLTD, at the hippocampo-prefrontal cortex (PFC) synapse. Impaired LTD at this synapse is disrupted in rodent models of schizophrenia and is thought to correlate with deficits in hippocampo-PFC communication observed in schizophrenia patients. It was assumed that M1 PAMs act through potentiation of canonical Gαq signaling, which leads to the activation of phospholipase C (PLC) and that activation of PLC is a key mechanism by which M1 activation induces multiple CNS effects. However, our lab and others have shown that M1 activation can also lead to activation of phospholipase D (PLD), independent of PLC activation. While most M1 PAMs potentiate coupling of M1 to both PLC and PLD, we reported the discovery of a novel M1 PAM that displays stimulus bias and thereby potentiates M1 coupling to PLC activation, while having no effect on PLD activity. I now present exciting data using novel highly selective PLD inhibitors suggesting that activation of PLD is required for induction of mLTD in the PFC. Whether potentiation of M1 coupling to PLD is required for M1 PAM-induced reversal of synaptic plasticity and behavioral deficits in a rodent model of cortical dysfunction in schizophrenia remains unknown. Completion of this research proposal will elucidate new basic biology and signaling downstream of the M1 mAChR while also providing key insight into the therapeutic potential of allosteric modulation of M1 as a potential treatment for the cognitive and negative symptoms observed in patients with schizophrenia.

项目概要 激活毒蕈碱乙酰胆碱受体 (mAChR) 的药物作为新疗法具有令人兴奋的潜力 精神分裂症患者的阴性症状和认知障碍。以前的 mAChR 激动剂 由于缺乏对个体 mAChR 亚型的选择性以及相关的不良反应，临床开发失败 随着外周 mAChR 的激活。我们现在已经发现并表征了高度选择性的正变构 单个 mAChR 亚型的调节剂 (PAM)，发现 M1 mAChR 的选择性 PAM 具有强大的稳定性 认知增强作用，并可能具有预测负面症状减少的作用。特别感兴趣的是 发现 M1 PAM 会增强海马前额叶的一种 M1 依赖性长期抑郁症，称为 mLTD 皮质 (PFC) 突触。在精神分裂症啮齿动物模型中，该突触受损的 LTD 受到破坏，并且被认为 与精神分裂症患者中观察到的海马-PFC 通讯缺陷相关。假设M1 PAM 通过增强经典 Gαq 信号传导发挥作用，从而激活磷脂酶 C (PLC)，并且 PLC 的激活是 M1 激活诱导多种 CNS 效应的关键机制。然而，我们的实验室和其他实验室 研究表明，M1 激活还可导致磷脂酶 D (PLD) 激活，与 PLC 激活无关。尽管 大多数 M1 PAM 增强 M1 与 PLC 和 PLD 的耦合，我们报告了一种新型 M1 PAM 的发现，它显示 刺激偏差，从而增强 M1 与 PLC 激活的耦合，同时对 PLD 活性没有影响。我现在提出 使用新型高选择性 PLD 抑制剂的令人兴奋的数据表明，PLD 的激活是诱导 PFC 中的 mLTD。 M1 PAM 诱导的突触逆转是否需要 M1 与 PLD 的偶联增强 精神分裂症皮质功能障碍啮齿动物模型的可塑性和行为缺陷仍然未知。完成 该研究计划的一部分将阐明 M1 mAChR 的新基础生物学和下游信号传导，同时还提供 对 M1 变构调节作为认知和消极治疗潜在治疗方法的治疗潜力的关键见解 在精神分裂症患者中观察到的症状。