Pro-Cognitive Action of CART Is Mediated via ERK in the Hippocampus
Pro-Cognitive Action of CART Is Mediated via ERK in the Hippocampus
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DOI：
10.1002/hipo.22608
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发表时间：
2016-10-01
期刊：
影响因子：
3.5
通讯作者：
Kokare, Dadasaheb M.
中科院分区：
文献类型：
--
作者：
Bharne, Ashish P.;Borkar, Chandrashekhar D.;Kokare, Dadasaheb M.
虽然可卡因和安非他明调节的转录肽（CART）在几个皮质和皮质下区域检测到，它在更高的功能中的作用在很大程度上被忽视。我们研究了CART在记忆形成中的意义，并测试了CART的下游作用是否涉及N-甲基-D-天冬氨酸（NMDA）激活的细胞外信号调节激酶（ERK）。新形成的记忆使用新物体识别测试，包括熟悉（T1）和选择试验（T2）。选择试验在两个时间点进行：采集后30 min（T2（30 min））和24 h（T2（24 h））。在选择试验（T2（30分钟））中，载体对照大鼠探索新物体的持续时间显著长于熟悉物体，表明记忆形成完整。然而，CART-抗体、U 0126 [ERK拮抗剂，均通过脑室内（icv）或海马内（ih）途径]或MK-801（NMDA拮抗剂;腹膜内）处理的大鼠花费较少的时间探索新对象; CART肽（icv或ih）无效。在T2（24小时）的选择试验期间，在溶剂对照大鼠中观察到新物体探索时间显著减少，表明健忘症。然而，在熟悉试验（T1）之前用CART治疗，即使在T2（24小时）也促进了对新对象的探索。用U 0126或MK-801预处理阻断CART的促认知样作用，表明NMDA-ERK通路参与CART的作用。进行对象熟悉试验的动物显示CART免疫反应性在齿状回的角氨3和多形层的细胞中急剧增加，以及内（ENT）和鼻周（PRH）皮质内的纤维。Western blot分析显示CART处理显著上调海马、ENT和PRH中磷酸化ERK 1/2的表达。U 0126或MK-801预处理后，这种作用减弱，表明通过NMDA受体激活ERK信号级联反应。因此，CART系统在再认记忆中起重要作用，其作用可能是通过ENT/PRH-海马回路中的NMDA受体-ERK信号通路介导的。(C)2016 Wiley Periodicals，Inc.
Although cocaine-and amphetamine-regulated transcript peptide (CART) is detected in several cortical and subcortical areas, its role in higher functions has been largely ignored. We examined the significance of CART in memory formation and tested if the downstream actions of CART involve N-methyl-D-aspartate (NMDA) activated extracellular signal-regulated kinase (ERK). Newly formed memory was evaluated using novel object recognition test consisting of familiarization (T1) and choice trials (T2). The choice trials were performed at two time points: 30-min (T2(30-min)) and 24-h (T2(24-h)) postacquisition. In choice trial (T2(30-min)), vehicle control rats explored the novel object for significantly longer duration than the familiar object indicating intact memory formation. However, CART-antibody, U0126 [ERK antagonist, both via intracerebroventricular (icv) or intrahippocampal (ih) route] or MK-801 (NMDA antagonist; intraperitoneal) treated rats spent less time exploring novel objects; CART peptide (icv or ih) was ineffective. During choice trial at T2(24-h), a significant decrease in novel object exploration time was noticed in vehicle control rats suggesting amnesia. However, treatment with CART, prior to familiarization trial (T1), promoted exploration of the novel object even at T2(24-h). Pretreatment with U0126 or MK-801 blocked pro-cognitive-like effect of CART suggesting involvement of NMDA-ERK pathway in CART's action. Animals subjected to the object familiarization trial showed a drastic increase in the CART-immunoreactivity in the cells of cornu ammonis 3 and polymorph layer of dentate gyrus, and fibers within ento-(ENT) and peri-rhinal (PRH) cortices. Western blot analysis revealed that CART treatment significantly up-regulated the expression of phospo-ERK1/2 in hippocampus, ENT and PRH. This effect was attenuated following pretreatment with U0126 or MK-801, suggesting the activation of ERK signaling cascade through NMDA receptors. Thus, CART system seems to play an important role in recognition memory and that these effects may be mediated by NMDA receptors-ERK signaling in the ENT/PRH-hippocampal circuit. (C) 2016 Wiley Periodicals, Inc.