Cholinergic and GABAergic Mechanisms in the Septohippocampal Pathway

隔海马通路中的胆碱能和 GABA 能机制

• 批准号: 7049997
• 负责人: Meenakshi Alreja
• 金额: $ 30.92万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7049997
• 关键词: GABA receptor; acetylcholine; biological signal transduction; brain mapping; brain metabolism; cGMP dependent protein kinase; central neural pathway /tract; cyclic AMP; cyclic GMP; electrophysiology; enzyme activity; gamma aminobutyrate; genetically modified animals; guanylate cyclase; hippocampus; immunocytochemistry; laboratory mouse; laboratory rat; neural transmission; neuropharmacology; neurotransmitter receptor; neurotransmitter transport; nitric oxide; nitric oxide synthase; phosphodiesterases; protein localization; protein protein interaction; reducing agents

DESCRIPTION (provided by applicant): Cognitive impairment is a serious health concern in the United States; it accompanies normal aging and dementing disorders such as Alzheimer's, as well as mental illnesses, such as schizophrenia and depression. Basic and clinical studies have long recognized the importance of acetylcholine (ACh) in cognition. The cholinergic muscarinic receptor antagonist, scopolamine, impairs learning and memory in humans and rodents primarily through actions on the brain septohippocampal neurons (SHNs). Acetylcholinesterase inhibitors, although limited in efficacy, are currently the best available treatment for Alzheimer's disease. The cyclic nucleotides, cAMP and cGMP, have also been implicated in learning and memory and certain phosphodiesterase (PDE) inhibitors that prevent cyclic nucleotide hydrolysis are cognitively beneficial and can also reverse scopolamine-induced cognitive deficits. While cAMP is effectively recruited by the stress-related neurotransmitter, CRF, the gaseous neural messenger, nitric oxide (NO) is the primary activator of the cGMP cascade. The SHNs, that give rise to the mnemonically important septohippocampal pathway receive CRF innervation, are endowed with CRF1 receptors and in preliminary electrophysiological studies were activated by CRF and cAMP analogs. Additionally, cholinergic SHNs belong to the unique population of CNS neurons that express the NO synthesizing enzyme. In preliminary studies GABA-type but not cholinergic-type SHNs, were activated by NO donors and cGMP analogs. NO imaging studies and PDE inhibitors also suggested the presence of a constitutive NO/cGMP tone as well as a cAMP tone in this brain region. We hypothesize that: 1) NO released from cholinergic SHNs behaves as an intercellular messenger to activate GABAergic SHNs through activation of the cGMP-kinase cascade and that cGMP actions are terminated primarily by the cGMP-specific PDE9; 2) CRF acting via CRF1 receptors and the cAMP-kinase cascade in cholinergic SHNs indirectly activates GABAergic SHNs through increased ACh release; 3) cAMP actions are terminated primarily by PDE4 and cross-talk between the cyclic nucleotide pathways occurs through dual-substrate PDE2 and possibly through a CRF-induced increase in NO synthesis. The above hypothesis will be tested using electrophysiological, immunohistochemical and NO visualization techniques in rodent brain slices.

描述（由申请人提供）：认知障碍在美国是一个严重的健康问题;它伴随着正常的衰老和痴呆症，如阿尔茨海默氏症，以及精神疾病，如精神分裂症和抑郁症。基础和临床研究早已认识到乙酰胆碱（ACh）在认知中的重要性。胆碱能毒蕈碱受体拮抗剂东莨菪碱主要通过作用于脑隔海马神经元（SHN）损害人类和啮齿动物的学习和记忆。乙酰胆碱酯酶抑制剂虽然疗效有限，但目前是治疗阿尔茨海默病的最佳方法。环核苷酸cAMP和cGMP也与学习和记忆有关，某些防止环核苷酸水解的磷酸二酯酶（PDE）抑制剂对认知有益，也可逆转东莨菪碱诱导的认知缺陷。虽然cAMP被应激相关的神经递质CRF（气态神经信使）有效地募集，但一氧化氮（NO）是cGMP级联的主要激活剂。SHN，引起记忆重要的隔海马通路接受CRF神经支配，被赋予CRF 1受体，并在初步的电生理研究中被CRF和cAMP类似物激活。此外，胆碱能SHN属于表达NO合成酶的CNS神经元的独特群体。在初步研究中，GABA型SHN而非胆碱能型SHN被NO供体和cGMP类似物激活。NO成像研究和PDE抑制剂也表明在该脑区存在组成性NO/cGMP张力以及cAMP张力。我们假设：1）胆碱能SHN释放的NO作为细胞间信使通过激活cGMP-激酶级联激活GABA能SHN，cGMP作用主要由cGMP特异性PDE 9终止; 2）CRF通过CRF 1受体和cAMP-激酶级联作用于胆碱能SHN，通过增加ACh释放间接激活GABA能SHN; 3）cAMP作用主要由PDE 4终止，并且环核苷酸途径之间的串扰通过双底物PDE 2并且可能通过CRF诱导的NO合成增加而发生。上述假设将在啮齿动物脑切片中使用电生理学、免疫组织化学和NO可视化技术进行测试。