Role of M4 mAChR in Modulating Hippocampal Neurotransmission

描述(申请人提供)：海马体是一个关键的皮质结构，在许多正常的生理过程中发挥重要作用，包括形成短期和长期记忆，也是包括阿尔茨海默病(AD)在内的某些神经疾病的主要病理部位。海马区的主要神经调节输入之一是基底前脑的胆碱能投射，该投射对记忆和注意机制至关重要，而该投射的退变在AD的病理过程中起着重要作用。胆碱能在海马区的传递主要由M受体(MAChRs)介导，mAChRs分为M1-M5亚型。M受体激动剂在海马区具有多种电生理效应，包括增强NMDA受体电流，减少抑制性和兴奋性突触传递，以及对锥体细胞的直接兴奋作用。然而，这些操作中涉及的特定mAChR子类型是未知的。确定每一种mAChR亚型在调节海马功能中的具体作用对于理解mAChR亚型在正常和病理条件下的参与至关重要。直到最近，由于缺乏亚型选择性探针，还不可能确定特定反应中涉及的mAChR亚型。然而，用抗体选择性地与五个克隆的mAChR亚型中的每一个反应的免疫细胞化学研究提供了有价值的见解，使我们能够提出关于mAChR亚型的假说，这些亚型介导了mAChR激活的各种突触前和突触后的效应。此外，我们现在已经在发现新型高选择性药物方面取得了重大进展，这些药物可以特异性地激活海马区主要的mAChR亚型M1或M4。这些试剂与最近开发的mAChR基因敲除小鼠相结合，提供了一个前所未有的机会来严格确定海马体和其他大脑区域中单个mAChR亚型的功能。我们提出了一系列研究，在这些研究中，我们将进一步表征高选择性的M1和M4激活剂，并与mAChR KO小鼠一起使用这些激活剂来确定哪些mAChR亚型介导了海马区mAChR激活的特定生理效应。选择性增强特定受体亚型胆碱能传递的药物可能有助于改善AD和其他记忆障碍患者的认知功能。

DESCRIPTION (provided by applicant): The hippocampus is a key cortical structure that plays an important role in a number of normal physiological processes including formation of short- and long-term memory, and is a primary site of pathology in certain neurological disorders including Alzheimer's disease (AD). One of the major neuromodulatory inputs to the hippocampus is a cholinergic projection from the basal forebrain which is critical for memory and attention mechanisms, and degeneration of this projection plays an important role in the pathology of AD. Cholinergic transmission in the hippocampus is mediated primarily by muscarinic acetylcholine receptors (mAChRs), which have been classified into M1 - M5 subtypes. Muscarinic agonists have a number of electrophysiological effects in the hippocampus including potentiation of NMDA receptor currents, reduction of both inhibitory and excitatory synaptic transmission, and direct excitatory effects on pyramidal cells. However, the specific mAChR subtypes involved in each of these actions are unknown. Determination of the specific roles of each of the mAChR subtypes in regulating hippocampal function will be critical for understanding the involvement of mAChR subtypes in both normal and pathological conditions. Until recently, it has not been possible to determine the mAChR subtypes involved in specific responses because of a lack of subtype-selective probes. However, immunocytochemistry studies with antibodies that selectively react with each of the five cloned mAChR subtypes have provided valuable insight that has allowed us to formulate hypotheses regarding the mAChR subtypes that mediate various pre- and postsynaptic effects of mAChR activation. Furthermore, we have now made major advances in discovery of novel highly selective pharmacological reagents that specifically activate either M1 or M4, the major mAChR subtypes in the hippocampus. These reagents, combined with recently developed mAChR knockout mice provide an unprecedented opportunity to rigorously determine the functions of individual mAChR subtypes in the hippocampus and other brain regions. We propose a series of studies in which we will further characterize highly selective activators of M1 and M4 and use these along with mAChR KO mice to determine which mAChR subtypes mediate specific physiological effects of mAChR activation in the hippocampal formation. Agents that selectively enhance cholinergic transmission at specific receptor subtypes could be useful for improving cognitive function in patients with AD and other memory disorders.