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

项目摘要 激活M胆碱乙酰胆碱受体(MAChRs)的药物具有令人兴奋的潜力，可作为新的治疗方法。 精神分裂症患者的阴性症状和认知障碍。以前的mAChR激动剂 由于缺乏对单个mAChR亚型的选择性和相关的不良反应，临床开发失败 外周mAChRs的激活。我们现在已经发现并表征了高度选择性的正变构 针对单个mAChR亚型的调制器(PAM)，并发现针对M1 mAChR的选择性PAM具有健壮性 增强认知的效果，并可能具有预测减少负面症状的行动。特别值得关注的是 发现M1 PAM增强了一种形式的M1依赖型长期抑郁，称为mLTD，位于海马额前区 皮质(PFC)突触。这种突触受损的LTD在精神分裂症的啮齿动物模型中被破坏，被认为是 与精神分裂症患者观察到的海马区-PFC通讯障碍有关。据推测，M1 PAMS通过增强典型的G-α-Q信号发挥作用，该信号导致磷脂酶C的激活。 PLC的激活是M1激活引起多种中枢神经系统效应的重要机制。然而，我们的实验室和其他人 已经证明，M1的激活也可以导致磷脂酶D(PLD)的激活，而不是PLC的激活。而当 大多数M1 PAM增强了M1与PLC和PLD的偶联，我们报告了一种新的M1 PAM的发现 刺激偏置，从而增强M1与PLC激活的偶联，而对PLD活性没有影响。我现在向大家介绍 使用新型高选择性PLD抑制剂的兴奋数据表明，PLD的激活是诱导 PFC中的mLTD。M1 PAM诱导的突触逆转是否需要增强M1与PLD的偶联作用 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不清楚。完成 将阐明M1 mAChR下游的新的基础生物学和信号，同时还提供 对M1变构调节作为认知和阴性潜在治疗方法的治疗潜力的关键洞察 精神分裂症患者的症状观察。

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.