Pathophysiology of the septo-hippocampal glutamatergic system

描述（由申请人提供）：阿尔茨海默病（AD）中隔神经元的变性导致皮质回路信息处理异常，从而导致脑功能障碍。隔膜调节原皮质（例如海马）和新皮质回路的活动，并且对于节律性皮质活动（例如海马θ节律）的启动和发生至关重要，该节律性皮质活动在处理感觉信息和记忆中起重要作用。直到最近，只有胆碱能和GABA能隔神经元被认为存在并投射到海马。我们的实验室表征了第三种隔神经元，它们投射到海马体，并使用谷氨酸作为神经递质。它们的功能和对AD的脆弱性仍然未知。由于突触参与学习和记忆过程，因此隔突触能神经元在AD损害的认知过程中起关键作用。我们的初步数据表明，隔β-淀粉样肽（Ap）的神经元被杀死。这种隔β-淀粉样肽神经元的损失是一个新的发现，可以彻底改变我们对AD的理解。本研究的目的是了解隔-海马神经元能系统的功能及其在AD发病中的作用。为了实现这一目标，我们假设，海马能神经元，而不是胆碱能神经元，提供了主要的隔兴奋性输入到海马体所需的θ节律的产生，促进塑料过程，这些海马能神经元的功能障碍起着核心作用，在隔变性和颞叶功能减退通常观察到的AD患者。因此，我们将使用免疫组织化学，体视学，神经元示踪剂，体外和体内电生理方法的组合来执行特定目标（SA），以确定：隔-海马突触能投射的突触后效应（SA 1），隔突触能神经元对淀粉样β肽（Ap）的脆弱性（SA 2），以及海马Theta节律和大不规则活动（LIA）中已鉴定的海马隔区神经元的放电模式及其由Ap（SA 3）引起的改变。总的来说，拟议的实验将使我们深入了解操纵隔海马能神经传递作为一种手段，调节海马网络的信息处理和恢复AD脆弱的认知过程，他们服务。

DESCRIPTION (provided by applicant): Degeneration of septal neurons in Alzheimer's disease (AD) results in abnormal information processing at cortical circuits and consequent brain dysfunction. The septum modulates the activity of archicortical (e.g. hippocampal) and neocortical circuits and is crucial to the initiation and occurrence of rhythmical cortical activities such as the hippocampal theta rhythm which plays an important role in processing sensory information and memory. Until recently, only cholinergic and GABAergic septal neurons were believed to exist and project to the hippocampus. Our laboratory characterized a third population of septal neurons that project to the hippocampus and use glutamate as a neurotransmitter. Their function and vulnerability to AD remains unknown. Because glutamatergic synapses are involved in learning and memory processes, septal glutamatergic neurons are critically positioned to play a key role in the cognitive processes impaired by AD. Our preliminary data indicate that septal glutamatergic neurons are killed by amyloid p peptides (Ap) This loss of septal glutamatergic neurons is a new finding that can revolutionize our understanding of AD. The goal of our research is to understand the function of the septo-hippocampal glutamatergic system and its involvement in AD. To achieve this goal, we hypothesize that glutamatergic neurons, rather than cholinergic neurons, provide the main septal excitatory input to the hippocampus necessary for the generation of a theta rhythm that facilitates plastic processes, and that the dysfunction of these glutamatergic neurons plays a central role in the septal degeneration and temporal lobe hypofunction typically observed in AD patients. Accordingly, we will use a combination of immunohistochemistry, stereology, neuronal tracers, in vitro and in vivo electrophysiological approaches to carry out specific aims (SA) that will determine: the postsynaptic effects of the septo-hippocampal glutamatergic projection (SA1), the vulnerability of the septal glutamatergic neurons to amyloid p peptides (Ap) (SA2), and the firing patterns of identified glutamatergic septal neurons during hippocampal theta rhythm and large irregular activity (LIA) and their alterations induced by Ap (SA3). Overall, the proposed experiments will give us insight into manipulating septal glutamatergic neurotransmission as a means of regulating information processing by hippocampal networks and restoring the AD-vulnerable cognitive processes they serve.