Down-Regulation of Neuregulin1/ErbB4 Signaling in the Hippocampus Is Critical for Learning and Memory
Down-Regulation of Neuregulin1/ErbB4 Signaling in the Hippocampus Is Critical for Learning and Memory
复制标题
海马 Neuregulin1/ErbB4 信号传导的下调对于学习和记忆至关重要
DOI：
10.1007/s12035-016-9956-5
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发表时间：
2017-08-01
影响因子：
5.1
通讯作者：
Gao, Tian-Ming
中科院分区：
文献类型：
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作者：
Tian, Jia;Geng, Fei;Gao, Tian-Ming
海马体功能对学习和记忆很重要，海马体功能障碍与精神分裂症等神经精神疾病的病理生理学有关。神经调节蛋白1(NRG1)和ErbB4是精神分裂症的两个易感基因，据报道，它们调节海马Schaffer侧支(SC)-CA1突触的长时程增强(LTP)。然而，关于海马区NRG1/ErbB4信号对学习记忆功能的影响，人们知之甚少。采用实时定量聚合酶链式反应和Western blotting检测NRG1和ErbB4的mRNA和蛋白水平。用药理学和遗传学方法对NRG1/ErbB4信号进行操作，然后通过Morris水迷宫、Y迷宫测试和新物体识别测试来评估学习和记忆行为。空间学习可降低海马区NRG1和ErbB4的表达。通过中和内源性NRG1或抑制/阻断ErbB4受体的活性，阻断海马CA1区的NRG1/ErbB4信号通路，增强海马依赖的空间学习、空间工作记忆和新的物体识别记忆。因此，外源性NRG1的应用损害了这些功能。更重要的是，小白蛋白中间神经元中ErbB4的特异性消融也改善了学习和记忆能力。本研究中对NRG1/ErbB4信号的操纵表明，NRG1/ErbB4在海马区的活动对学习和记忆至关重要。这些发现可能为精神分裂症的病理生理机制提供新的见解，并为以认知功能进行性下降为特征的阿尔茨海默病的治疗提供新的靶点。
Hippocampal function is important for learning and memory, and dysfunction of the hippocampus has been linked to the pathophysiology of neuropsychiatric diseases such as schizophrenia. Neuregulin1 (NRG1) and ErbB4, two susceptibility genes for schizophrenia, reportedly modulate long-term potentiation (LTP) at hippocampal Schaffer collateral (SC)-CA1 synapses. However, little is known regarding the contribution of hippocampal NRG1/ErbB4 signaling to learning and memory function. Here, quantitative real-time PCR and Western blotting were used to assess the mRNA and protein levels of NRG1 and ErbB4. Pharmacological and genetic approaches were used to manipulate NRG1/ErbB4 signaling, following which learning and memory behaviors were evaluated using the Morris water maze, Y-maze test, and the novel object recognition test. Spatial learning was found to reduce hippocampal NRG1 and ErbB4 expression. The blockade of NRG1/ErbB4 signaling in hippocampal CA1, either by neutralizing endogenous NRG1 or inhibiting/ablating ErbB4 receptor activity, enhanced hippocampus-dependent spatial learning, spatial working memory, and novel object recognition memory. Accordingly, administration of exogenous NRG1 impaired those functions. More importantly, the specific ablation of ErbB4 in parvalbumin interneurons also improved learning and memory performance. The manipulation of NRG1/ErbB4 signaling in the present study revealed that NRG1/ErbB4 activity in the hippocampus is critical for learning and memory. These findings might provide novel insights on the pathophysiological mechanisms of schizophrenia and a new target for the treatment of Alzheimer’s disease, which is characterized by a progressive decline in cognitive function.