Pathophysiology of the septo-hippocampal glutamatergic system

间隔海马谷氨酸能系统的病理生理学

• 批准号: 8128414
• 负责人: Luis V. Colom
• 金额: $ 32.55万
• 依托单位: UNIV/TEXAS BROWNSVILLE & SOUTHMOST COLL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8128414
• 关键词: Adult; Affect; Alzheimer' s Disease; Amyloid; Area; Axon; Bathing; Brain; Cells; Clinical; Cognition; Cognitive; Data; Dementia; Depressed mood; Development; Disease; Electric Stimulation; Electrodes; Functional disorder; Generations; Glutamates; Goals; Hippocampus (Brain); Immunohistochemistry; Immunotoxins; Impaired cognition; In Vitro; Injection of therapeutic agent; Injury; Interneurons; Intervention; Laboratories; Learning; Lesion; Measurement; Medial; Mediating; Memory; Memory impairment; Modeling; Molecular; Muscarinics; Neurons; Neurotransmitters; Pathology; Patients; Pattern; Peptides; Physiological; Physiology; Plastics; Play; Population; Positioning Attribute; Predisposition; Preparation; Procedures; Process; Property; Rattus; Research; Role; Sensory Process; Site; Slice; Structure; Synapses; Synaptic Transmission; System; Temporal Lobe; Testing; Therapeutic; Theta Rhythm; Time; Toxic effect; Tracer; Work; age related; basal forebrain cholinergic neurons; base; biotinylated dextran amine; brain research; cholinergic; cholinergic neuron; cognitive function; extracellular; improved functioning; in vivo; information processing; injured; innovation; insight; killings; memory process; neocortical; neurotransmission; novel; peptide A; postsynaptic; prevent; research study; septohippocampal

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.

描述（由申请人提供）：阿尔茨海默病（AD）中隔神经元变性导致皮质回路信息处理异常，从而导致脑功能障碍。中隔调节皮层（如海马）和新皮层回路的活动，对有节奏的皮层活动（如海马θ节律）的开始和发生至关重要，而海马θ节律在处理感觉信息和记忆中起重要作用。直到最近，只有胆碱能神经元和gaba能神经元被认为存在并投射到海马体。我们的实验室描述了第三种间隔神经元，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。由于谷氨酸能突触参与学习和记忆过程，间隔谷氨酸能神经元在AD损害的认知过程中发挥关键作用。我们的初步数据表明，间隔谷氨酸能神经元被淀粉样p肽（Ap）杀死。这种间隔谷氨酸能神经元的丢失是一个新的发现，可以彻底改变我们对阿尔茨海默病的理解。我们的研究目的是了解中隔-海马谷氨酸系统的功能及其在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，向海马提供主要的间隔兴奋输入，这是产生促进可塑性过程的θ节奏所必需的，并且这些谷氨酸能神经元的功能障碍在AD患者中典型的间隔变性和颞叶功能减退中起着核心作用。因此，我们将结合免疫组织化学，体视学，神经元示踪剂，体外和体内电生理方法来进行特定目的（SA），这将确定：中隔-海马谷氨酸能投射（SA1）的突触后效应，中隔谷氨酸能神经元对淀粉样p肽（Ap）的易感性（SA2），以及在海马节律和大不规则活动（LIA）期间鉴定的谷氨酸能中隔神经元的放电模式及其由Ap引起的改变（SA3）。总的来说，我们提出的实验将使我们深入了解操纵间隔谷氨酸能神经传递作为调节海马网络信息处理和恢复ad易感认知过程的手段。

项目成果

Probability of A-channel rectification (Commentary on Johnston et al., 2008).

• DOI: 10.1111/ejn.15804
• 发表时间: 2022-12
• 期刊: The European journal of neuroscience

Probability that there is a mammalian counterpart of cardiac clock in insects.

• DOI: 10.1002/arch.21867
• 发表时间: 2022-05
• 期刊: Archives of insect biochemistry and physiology
• 影响因子: 2.2

Addictive neurons.

令人上瘾的神经元。

• 发表时间: 2017
• 期刊: Therapeutic targets for neurological diseases
• 作者: Kodirov,SodikdjonA

Nicotine-Mediated ADP to Spike Transition: Double Spiking in Septal Neurons.

• DOI: 10.1007/s00232-015-9853-2
• 发表时间: 2016-04
• 期刊: The Journal of membrane biology
• 作者: Kodirov SA;Wehrmeister M;Colom L
• 通讯作者: Colom L

Functioning of K channels during sleep.

• DOI: 10.1002/arch.21884
• 发表时间: 2022-06
• 期刊: ARCHIVES OF INSECT BIOCHEMISTRY AND PHYSIOLOGY
• 影响因子: 2.2
• 作者: Kodirov, Sodikdjon A.