Muscarinic Receptor Induced LTD in Rat Hippocampus

描述（由申请人提供）：海马的胆碱能神经支配是某些形式的学习和记忆所必需的。胆碱能隔-海马传入纤维的变性是阿尔茨海默病（Alzheimer 'sDisease，AD）的标志之一，认知功能下降的严重程度与胆碱能损害有关。乙酰胆碱（ACh），海马突触可塑性，学习和记忆，和AD之间的重叠刺激ACh调节海马功能的机制的调查，因为这些机制的改变可能是AD的一些认知缺陷的基础。我们对突触功能和可塑性的胆碱能调节的理解尚不清楚，因此，除非这些机制被解开，否则我们治疗或预防胆碱能依赖性认知衰退的能力将保持次优。 我们的特点是在体外大鼠海马CA 1区的一种形式的长期抑郁症（mLTD）是通过激活M1毒蕈碱受体（M1 AChRs）诱导。 mLTD是活性和NMDA受体依赖性的，并且被低频刺激诱导的LTD阻断。MI AChR的突触前与突触后位置尚不清楚，下游事件尚未确定。我们已经发现，海马胆碱能去神经支配（CD），一个模型的胆碱能功能减退，发生在AD，防止诱导mLTD。 有趣的是，CD刺激交感神经轴突长入海马，并通过未知的机制将mLTD恢复到对照水平。 在这里，我们将测试的假设，mLTD需要激活的信号级联连接到M1乙酰胆碱受体和海马胆碱能去神经改变诱导mLTD通过改变耦合M1乙酰胆碱受体的信号转导通路。 我们将使用脑切片中的电生理学与药理学工具、生物化学和免疫组织化学的组合来实现所提出的目标：1）检查mLTD的细胞机制; 2）检查CD和交感神经向内生长如何改变mLTD诱导/表达; 3）检查去甲肾上腺素诱导的突触传递变化与mLTD相互作用。预计本研究的结果将为设计胆碱能损伤症状的新治疗策略提供见解。

DESCRIPTION (provided by applicant): Cholinergic innervation of hippocampus is required for some forms of learning and memory. The degeneration of cholinergic septohippocampal afferents is one hallmark of Alzheimer's Disease (AD) and the severity of cognitive decline is correlated with cholinergic impairment. The overlap between acetylcholine (ACh), hippocampal synaptic plasticity, learning and memory, and AD stimulates investigations into mechanisms by which ACh modulates hippocampal function, since alterations in these mechanisms may underlie some cognitive deficiencies in AD. Our understanding of cholinergic modulation of synaptic function and plasticity is not clear, hence our ability to treat or prevent cholinergic dependent cognitive decline will remain sub-optimal unless these mechanisms are unraveled. We have characterized a form of long-term depression (mLTD) in the CA1 region of rat hippocampus in vitro that is induced via activation of M1 muscarinic receptors (M1 AChRs). mLTD is activity and NMDA receptor dependent and is occluded by LTD induced by low frequency stimulation. The pre vs. postsynaptic location of the MI AChRs is unknown and the downstream events have not been identified. We have found that cholinergic denervation (CD) of hippocampus, a model of cholinergic hypofunction that occurs in AD, prevents the induction of mLTD. Interestingly, CD stimulates ingrowth of sympathetic axons into hippocampus and restores mLTD to control levels through an unknown mechanism. Herein we will test the hypothesis that mLTD requires activation of the signaling cascade linked to M1 AChRs and that cholinergic denervation of hippocampus alters the induction of mLTD by altering the coupling of M1 AChRs to their signal transduction pathway. We will use a combination of electrophysiology in brain slices together with pharmacological tools, biochemistry and immunohistochemistry to carry out the proposed aims: 1) examine the cellular mechanisms underlying mLTD; 2) will examine how CD and sympathetic ingrowth alters mLTD induction/expression; 3) examine norepinephrine-induced changes in synaptic transmission interact with mLTD. It is expected that results from this study will provide insight into designing novel therapeutic strategies for symptoms of cholinergic impairment.