Roles and mechanisms of neurotensin in learning and memory

神经降压素在学习记忆中的作用和机制

• 批准号: 8706231
• 负责人: Saobo Lei
• 金额: $ 34.5万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8706231
• 关键词: APP-PS1; Action Potentials; Affinity; Agonist; Alanine; Alzheimer' s Disease; American; Amino Acids; Bathing; Blood - brain barrier anatomy; Cell model; Cells; Cholinesterase Inhibitors; Cognitive; Data; Dementia; Deterioration; Disease; Dose; Elderly; Frequencies; G-Protein-Coupled Receptors; Individual; Knockout Mice; Learning; Long-Term Potentiation; Mediating; Memantine; Membrane; Memory; Microinjections; Molecular; Mus; Mutate; NMDA receptor antagonist; Neurons; Neurotensin; Neurotensin Receptors; Pathway interactions; Patients; Peptides; Performance; Peripheral; Pharmaceutical Preparations; Phospholipase C; Phosphorylation; Phosphorylation Inhibition; Phosphorylation Site; Physiological; Potassium Channel; Protein Isoforms; Protein Kinase C; Role; Series; Serine; Serine Phosphorylation Site; Signal Transduction; Slice; Structure; Subcutaneous Injections; Synapses; Synaptic Transmission; Testing; Therapeutic; Transmembrane Domain; Whole-Cell Recordings; citrate carrier; clinically significant; density; entorhinal cortex; improved; in vivo; mouse model; mutant; neuronal excitability; novel strategies; postsynaptic; public health relevance; receptor; research study; response; small molecule

DESCRIPTION (provided by applicant): Neurotensin (NT) is a tridecapeptide widely distributed in the CNS including the entorhinal cortex (EC) which is crucial for learning and memory and undergoes the earliest pathological alterations in Alzheimer's Disease (AD). Whereas high density of NT receptors has been detected in the EC, the roles of NT in learning and memory and in AD have not been determined. AD is characterized by progressive deterioration of cognitive performance and afflicts ~5.3 million Americans. The current drugs available for the treatment of AD including the cholinesterase inhibitors and the partial NMDA receptor antagonist memantine only benefit a subset of patients for a limited period. Therefore, identifying and characterizing additional mechanisms through which cognitive deficiency can be improved still represent an important approach for AD therapy. We propose to study the roles and the underlying mechanisms of NT in facilitation of spatial memory in the EC and then test the possibility of using NT receptor agonists for AD therapy in AD mouse model. We have substantial preliminary data demonstrating that NT induced Long-Term Excitation (LTE) of neuronal excitability in the EC. We also demonstrated that microinjection of NT into the EC facilitated spatial learning and memory in Barnes Maze Test. The objective of this project is to determine the involved cellular and molecular mechanisms by testing the hypothesis that NT induces LTE of neuronal excitability and facilitates spatial learning and memory via NTS1/PLC/PKC-dependent inhibition of TREK-2 channels. Aim 1 will identify mechanisms underlying NT-induced LTE of neuronal excitability in the EC. We will identify the roles of PKC isoforms, PKC phosphorylation sites in TREK-2 channels and PKC- dependent phosphorylation of TREK-2 channels in vivo in NT-mediated LTE in the EC. Aim 2 will determine the mechanisms whereby NT facilitates spatial learning and memory by testing the hypothesis that NT augments spatial learning and memory via activation of PLC and PKC pathway resulting in inhibition of TREK-2 channels in the EC by using both pharmacological approach and knockout mice. Aim 3 will identify effects of NT and PD149163, a small molecule NTS1 agonist that can penetrate the blood-brain barrier on spatial learning and memory in APP/PS1 mice, an AD mouse model. We expect to determine the cellular and molecular mechanisms whereby NT facilitates spatial learning and memory and identify a novel approach of using NTS1 agonists for AD therapy in AD mouse model.

描述（由申请人提供）：神经降压素（NT）是一种广泛分布于包括内嗅皮层（EC）在内的CNS中的十三肽，其对于学习和记忆至关重要并且经历阿尔茨海默病（AD）中最早的病理学改变。尽管在EC中检测到高密度的NT受体，但NT在学习和记忆以及AD中的作用尚未确定。AD的特征在于认知表现的进行性恶化，并且折磨约530万美国人。目前可用于治疗AD的药物，包括胆碱酯酶抑制剂和部分NMDA受体拮抗剂美金刚，仅在有限的时间内使一部分患者受益。因此，识别和表征可以改善认知缺陷的其他机制仍然是AD治疗的重要方法。本研究拟探讨NT在EC空间记忆易化中的作用及其机制，并在AD小鼠模型上探讨NT受体激动剂治疗AD的可能性。我们有大量的初步数据表明，NT诱导的长期兴奋（LTE）的EC神经元兴奋性。在巴恩斯迷宫实验中，我们还证实了EC内微量注射NT可促进空间学习记忆。本项目的目的是通过验证NT诱导神经元兴奋性LTE并通过NTS 1/PLC/PKC依赖性抑制TREK-2通道促进空间学习和记忆的假设来确定所涉及的细胞和分子机制。目的1将确定潜在的NT诱导的LTE的神经元兴奋性EC的机制。我们将在EC中确定PKC亚型、TREK-2通道中的PKC磷酸化位点和TREK-2通道的PKC依赖性磷酸化在NT介导的LTE中的作用。目的2通过药理学方法和基因敲除小鼠实验验证NT通过激活PLC和PKC通路抑制TREK-2通道增强EC空间学习记忆的假说，以确定NT促进空间学习记忆的机制。目的3：研究NT和PD 149163对AD小鼠模型APP/PS1小鼠空间学习记忆的影响。我们希望确定NT促进空间学习和记忆的细胞和分子机制，并确定一种新的方法，使用NTS 1激动剂治疗AD小鼠模型。