Muscarinic Receptor Induced LTD in Rat Hippocampus

描述(申请人提供)：某些形式的学习和记忆需要海马胆碱能神经支配。胆碱能隔-海马区传入纤维变性是阿尔茨海默病(AD)的标志之一，认知功能减退的严重程度与胆碱能损伤有关。乙酰胆碱(ACh)、海马突触可塑性、学习记忆和AD之间的重叠刺激了对ACh调节海马功能的机制的研究，因为这些机制的改变可能是AD一些认知缺陷的基础。我们对胆碱能调节突触功能和可塑性的了解尚不清楚，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仍将是次优的。我们在体外研究了大鼠海马CA1区的一种形式的长期抑郁(MLTD)，这种抑郁是通过激活M1毒碱受体(M1 AChRs)诱导的。MLTD是活动和NMDA受体依赖的，并被低频刺激诱导的LTD阻断。MI AChRs突触前和突触后的位置尚不清楚，下游事件也尚未确定。我们发现，海马区的胆碱能去神经(CD)--一种发生在AD中的胆碱能功能低下的模型--可以阻止mLTD的诱导。有趣的是，Cd通过一种未知的机制刺激交感神经轴突进入海马区，并使mLTD恢复到控制水平。在这里，我们将检验一种假设，即mLTD需要激活与M1AChRs相关的信号级联，而海马胆碱能去神经通过改变M1AChRs与其信号转导途径的耦合来改变mLTD的诱导。我们将结合脑片上的电生理学以及药理学工具、生物化学和免疫组织化学来实现拟议的目标：1)研究mLTD的细胞机制；2)研究CD和交感神经生长如何改变mLTD的诱导/表达；3)研究去甲肾上腺素诱导的突触传递与mLTD的相互作用。预计这项研究的结果将为设计针对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.