Role of M4 mAChR in Modulating Hippocampal Neurotransmission

描述（由申请人提供）：海马体是关键的皮质结构，其在包括短期和长期记忆的形成在内的许多正常生理过程中起重要作用，并且是包括阿尔茨海默病（AD）在内的某些神经障碍的主要病理部位。海马的主要神经调节输入之一是来自基底前脑的胆碱能投射，其对于记忆和注意力机制至关重要，并且该投射的退化在AD的病理学中起重要作用。海马中的胆碱能传递主要由毒蕈碱乙酰胆碱受体（mAChR）介导，其已被分类为M1 - M5亚型。毒蕈碱激动剂在海马中具有许多电生理学效应，包括NMDA受体电流的增强、抑制性和兴奋性突触传递的减少以及对锥体细胞的直接兴奋性效应。然而，具体的mAChR亚型参与这些行动是未知的。确定每个mAChR亚型在调节海马功能中的特定作用对于理解mAChR亚型在正常和病理条件下的参与将是至关重要的。直到最近，由于缺乏亚型选择性探针，还不可能确定参与特异性反应的mAChR亚型。然而，免疫细胞化学研究与抗体，选择性地与每一个克隆的mAChR亚型提供了有价值的见解，使我们能够制定假说的mAChR亚型介导的各种前和突触后mAChR激活的影响。此外，我们现在在发现新的高选择性药理学试剂方面取得了重大进展，这些试剂特异性地激活海马中的主要mAChR亚型M1或M4。这些试剂与最近开发的mAChR敲除小鼠相结合，为严格确定海马和其他脑区中单个mAChR亚型的功能提供了前所未有的机会。我们提出了一系列的研究中，我们将进一步表征M1和M4的高选择性激活剂，并使用这些沿着与mAChR基因敲除小鼠，以确定哪些mAChR亚型介导的mAChR激活海马结构中的特定生理效应。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.