Pathophysiology of the septo-hippocampal glutamatergic system

描述(申请人提供)：阿尔茨海默病(AD)中隔神经元的退化导致皮质回路的信息处理异常，从而导致大脑功能障碍。隔对中枢(如海马区)和新皮质回路的活动进行调节，对节律性皮质活动的启动和发生至关重要，如在处理感觉信息和记忆中起重要作用的海马theta节律。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区。我们的实验室鉴定了第三组隔区神经元的特征，这些神经元投射到海马体，并使用谷氨酸作为神经递质。它们的功能和对AD的脆弱性仍不清楚。由于谷氨酸能突触参与学习和记忆过程，隔区谷氨酸能神经元在阿尔茨海默病受损的认知过程中发挥关键作用。我们的初步数据表明，隔区谷氨酸能神经元被淀粉样p肽(AP)杀死，这种隔区谷氨酸能神经元的丧失是一项新的发现，可以彻底改变我们对AD的理解。我们研究的目的是了解隔-海马谷氨酸能系统的功能及其在AD中的作用。为了实现这一目标，我们假设谷氨酸能神经元，而不是胆碱能神经元，为海马区提供主要的隔区兴奋性输入，以产生促进可塑性过程的theta节律，并且这些谷氨酸能神经元的功能障碍在AD患者通常观察到的间隔变性和颞叶功能减退中发挥核心作用。因此，我们将结合免疫组织化学、体视学、神经元示踪、体外和体内电生理方法进行特定的AIMS(SA)研究，以确定：隔-海马谷氨酸能投射(SA1)的突触后效应、隔谷氨酸能神经元对淀粉样肽(AP)(SA2)的易感性，以及在海马theta节律和大不规则活动(LIA)期间已识别的谷氨酸能隔神经元的放电模式及其由AP(SA3)诱导的改变。总体而言，拟议的实验将使我们深入了解操纵隔区谷氨酸能神经传递作为一种通过海马网调节信息处理的手段，并恢复它们所服务的易受AD影响的认知过程。

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.