Cholinergic and GABAergic Mechanisms in the Septohippocampal Pathway

描述(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。胆碱能毒碱能受体拮抗剂东莨菪碱主要通过对大脑中隔海马神经元(SHN)的作用来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，但目前是阿尔茨海默病的最佳治疗方法。环核苷酸cAMP和cGMP也与学习和记忆有关，某些阻止环核苷酸水解的磷酸二酯酶(PDE)抑制剂对认知有益，也可以逆转东莨菪碱引起的认知障碍。CAMP被应激相关的神经递质CRF(气态神经信使)有效地招募，而一氧化氮(NO)是cGMP级联反应的主要激活剂。产生记忆上重要的隔-海马通路的SHN接受CRF神经支配，被赋予CRF1受体，在初步的电生理研究中，CRF和cAMP类似物激活了SHN。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，NO供体和cGMP类似物激活了GABA类型的SHN，而不是胆碱能类型的SHN。没有成像研究和PDE抑制剂也表明在这个大脑区域存在结构性的NO/cGMP音调和cAMP音调。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作用主要被cGMP特异性的PDE9终止；2)CRF通过CRF1受体作用，而胆碱能SHN中的cAMP-KK级联通过增加ACh释放间接激活GABA能SHN；3)cAMP作用主要由PDE4终止，环核苷酸通路之间的串扰通过双底物PDE2发生，可能通过CRF诱导的NO合成增加。上述假说将在啮齿动物脑片中使用电生理、免疫组织化学和非可视化技术进行验证。

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.