PKMζ参与慢性刺激诱导ApoE2转基因鼠抑郁状态的神经环路形成

项目名称： PKMζ参与慢性刺激诱导ApoE2转基因鼠抑郁状态的神经环路形成

项目编号： No.91232709

项目类型： 重大研究计划

立项/批准年度： 2013

项目学科： 神经系统疾病、精神疾病

项目作者： 陈晓春

作者单位： 福建医科大学

项目金额： 70万元

中文摘要： 临床研究显示载脂蛋白E2(ApoE2)基因型人群可增加抑郁症发生的风险，但机制尚不明确。近年研究发现非典型蛋白激酶C异构体PKMζ的抑制剂可抑制突触传递和长时程增强形成，但PKMζ影响情感障碍神经环路的机制还不清楚。本项目拟通过慢性不可预见的温和应激诱导，以ApoE-KO和ApoE3/4基因型小鼠作为对照，观察ApoE2基因型小鼠抑郁状态的发生情况；结合脑片电生理和脑微透析技术，在“前额叶-杏仁核-海马-丘脑和下丘脑”神经环路层面，探讨慢性应激引起抑郁易感型ApoE2转基因鼠兴奋性/抑制性突触传递功能紊乱的机制；并借助分子生物学、电生理及行为学等方法，分析PKMζ在抑郁易感型ApoE2转基因鼠异常神经环路形成中的作用。本研究将为“ApoE遗传背景-慢性应激诱导”抑郁症小鼠模型的建立奠定基础，并有助于深入揭示抑郁症的发病机制，为新型抗抑郁药物研发提供新的靶点。

中文关键词： 抑郁症；学习记忆；载脂蛋白E4；糖代谢；GABA能中间神经元

英文摘要： Clinical studies have shown the risk of depression disorder increases in the population with apolipoprotein E2 (ApoE2) gene, but the mechanism is not clear. PKMζ is an isomer of atypical protein kinase C (PKCs) subgroup. Recent studies have found the inhibitors of PKMζ inhibit the synaptic transmission and long-term potentiation(LTP). However, it remains unclear about the neural circuit of PKMζ affecting mood disorder. In the study, chronic unpredicted mild stress (CUMS) is used to establish rat depression model. Then we compare the incidence of depression behaviors in ApoE-KO and ApoE2/3/4-TR gene background rats separately to explore the susceptibility of ApoE2 transgenic rat to depression. To investigate the mechanism underlying the vulnerability of ApoE2 to depression, the excitatory/inhibitory synaptic transmission is measured by brain microdialysis and electrophysiological techniques in the brain areas (including the prefrontal cortex, amygdala, hippocampus, thalamus and hypothalamus) closely related with depression disorder. Then we examine the difference of PKMζ expression and function in neural circuit in the rat depression models with ApoE-KO/2/3/4 gene background. This study will help to establish a stable rat depression model based on ApoE gene background – chronic stress interaction, illustrate th

英文关键词： major depressive disorder；learning and memory；Apoliprotein E4；glucose metabolism；GABAergic interneuron