Enhanced interaction among ErbB4, PSD-95 and NMDAR by chronic MK-801 treatment is associated with behavioral abnormalities
Enhanced interaction among ErbB4, PSD-95 and NMDAR by chronic MK-801 treatment is associated with behavioral abnormalities
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长期 MK-801 治疗增强 ErbB4、PSD-95 和 NMDAR 之间的相互作用与行为异常相关
DOI：
10.1016/j.pbb.2013.04.008
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发表时间：
2013-07-01
影响因子：
3.6
通讯作者：
Si, Tian-Mei
中科院分区：
文献类型：
--
作者：
Li, Ji-Tao;Feng, Yu;Si, Tian-Mei
神经调节蛋白1 (NRG1)-ErbB4信号通路与精神分裂症的病理生理有关。最近的研究表明，该途径可能通过突触后支架蛋白PSD-95与n -甲基- d -天冬氨酸受体（NMDAR）相互作用。鉴于NMDAR功能障碍在精神分裂症中的主导作用，这种相互作用特别有趣。本研究采用免疫沉淀法研究了慢性NMDAR阻断对大鼠前额皮质和海马两系统功能相互作用的短期和长期影响。成年雄性Wistar大鼠腹腔注射MK-801 （0.25 mg/kg）或生理盐水28 d。最后一次注射24小时后，ErbB4与PSD-95和NMDAR的关联在前额皮质增强，而在海马中仅磷酸化的ErbB4相对于ErbB4增加。然而，这些影响在最后一次MK-801治疗后12天未被检测到，表明这些变化的可逆性。我们还研究了慢性MK-801治疗对运动、脉冲前抑制、识别记忆和空间工作记忆的影响。结果显示，这种治疗导致运动活动减少，在中央舞台的探索减少，惊吓程度升高，表明焦虑样表型。综上所述，我们的研究结果表明NRG1-ErbB4信号可以通过重复的NMDAR阻断来调节，并为两种信号通路之间的串扰提供了进一步的证据。(C) 2013爱思唯尔公司版权所有。
The neuregulin1 (NRG1)-ErbB4 signaling pathway has been implicated in the pathophysiology of schizophrenia. Recent studies suggest that this pathway may interact with the N-methyl-D-aspartate receptor (NMDAR) via the postsynaptic scaffold protein PSD-95. This interaction is of particular interest given the leading role of the NMDAR hypofunction in schizophrenia. The present study investigated the short- and long-term effects of chronic NMDAR blockade on the functional interaction between the two systems in rat prefrontal cortex and hippocampus using immunoprecipitation. Adult male Wistar rats were treated intraperitoneally with MK-801 (0.25 mg/kg) or saline for 28 days. Twenty-four hours after the last injection, the associations of ErbB4 with PSD-95 and NMDAR were enhanced in the prefrontal cortex, whereas only phosphorylated-ErbB4 relative to ErbB4 was increased in the hippocampus. These effects, however, were not detectable 12 days after the last MK-801 treatment, indicating the reversible nature of these changes. We also investigated the effects of chronic MK-801 treatment on locomotion, prepulse inhibition, recognition memory, and spatial working memory. The results showed that this treatment led to decreased locomotor activity, reduced exploration in the center arena, and elevated startle magnitudes, indicating an anxiety-like phenotype. Taken together, our findings suggest that the NRG1-ErbB4 signaling could be modulated by repeated NMDAR blockade, and provide further evidence for the cross-talk between the two signaling pathways. (C) 2013 Elsevier Inc. All rights reserved.