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

项目摘要 激活毒蕈碱型乙酰胆碱受体（mAChR）的药剂具有令人兴奋的潜力，可作为新的治疗药物， 精神分裂症患者的阴性症状和认知障碍。既往mAChR激动剂 由于缺乏对单个mAChR亚型的选择性和相关的不良反应， 与外周mAChR的激活有关。我们现在已经发现并表征了高度选择性的正变构 研究人员对单个mAChR亚型的PAM进行了研究，发现M1 mAChR的选择性PAM具有鲁棒性， 认知增强作用，并可能具有预测阴性症状减少的作用。特别感兴趣的是 发现M1 PAM增强了一种M1依赖性长期抑郁症，称为mLTD，在前额叶皮层 皮质（PFC）突触。在啮齿动物精神分裂症模型中，这个突触的LTD受损被破坏， 与在精神分裂症患者中观察到的大脑前额叶皮层-前额叶皮层通讯缺陷相关。假设M1 PAM通过增强经典Gαq信号传导起作用，这导致磷脂酶C（PLC）的激活， 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 已经表明M1的激活也可以导致磷脂酶D（PLD）的激活，而不依赖于PLC的激活。而 大多数M1 PAM增强了M1与PLC和PLD的偶联，我们报道了一种新的M1 PAM的发现， 刺激偏置，从而加强M1耦合PLC激活，而对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 M1与PLD偶联的增强是否是M1 PAM诱导的突触逆转所必需的。 精神分裂症中皮质功能障碍的啮齿动物模型的可塑性和行为缺陷仍然未知。完成 这项研究计划的一部分将阐明M1 mAChR下游的新的基础生物学和信号传导，同时也提供了 对M1变构调节作为认知和负性疾病潜在治疗的治疗潜力的关键见解 精神分裂症患者的症状。

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.