The extracellular signal-regulated kinase pathway contributes to the control of behavioral excitement
The extracellular signal-regulated kinase pathway contributes to the control of behavioral excitement
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DOI：
10.1038/sj.mp.4002135
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发表时间：
2009-04-01
影响因子：
11
通讯作者：
Chen, G.
中科院分区：
文献类型：
--
作者：
Engel, S. R.;Creson, T. K.;Chen, G.
细胞外信号调节激酶 (ERK) 通路介导中枢神经系统的神经元可塑性。情绪稳定剂锂和丙戊酸盐激活前额皮质和海马中的 ERK 通路，并增强 ERK 通路介导的神经突生长、神经元存活和海马神经发生。在这里，我们研究了 ERK 通路在与双相情感障碍相关的行为可塑性中的作用。 ERK1消融的小鼠在前额皮质和纹状体中获得了ERK底物RSK1的磷酸化减少，但在海马或小脑中没有，这表明消融引起的大脑区域特异性ERK信号传导缺陷。 ERK1 消融产生了类似于精神兴奋剂引起的行为兴奋特征。该特征的特征是多动、增强的目标导向活动和增加的与快乐相关的活动，并具有潜在的有害后果。 ERK1 缺失的小鼠在多项测试中表现出过度活跃，并且在强迫游泳测试中对行为绝望具有抵抗力。这些小鼠表现出更多的家笼自愿轮跑活动、在大竞技场中饲养以及在高架十字迷宫中张开手臂参观。丙戊酸和奥氮平（而非锂）治疗降低了 ERK1 消除小鼠的基线活性。所有三种治疗均减轻了安非他明引起的消融小鼠的过度活跃。这些数据表明 ERK1 信号传导深刻参与行为兴奋和抗躁狂药物的行为作用。 ERK 通路扰动对双相情感障碍的易感性、情绪转换机制和症状病理生理学的影响程度需要进一步研究。情绪稳定剂是否通过共同机制对躁狂的情绪、思想和行为症状产生临床作用还需要进一步研究。
The extracellular signal-regulated kinase (ERK) pathway mediates neuronal plasticity in the CNS. The mood stabilizers lithium and valproate activate the ERK pathway in prefrontal cortex and hippocampus and potentiate ERK pathway-mediated neurite growth, neuronal survival and hippocampal neurogenesis. Here, we examined the role of the ERK pathway in behavioral plasticity related to facets of bipolar disorder. Mice with ERK1 ablation acquired reduced phosphorylation of RSK1, an ERK substrate, in prefrontal cortex and striatum, but not in hippocampus or cerebellum, indicating the ablation-induced brain region-specific ERK signaling deficits. ERK1 ablation produced a behavioral excitement profile similar to that induced by psychostimulants. The profile is characterized by hyperactivity, enhanced goal-directed activity and increased pleasure-related activity with potential harmful consequence. ERK1-ablated mice were hyperactive in multiple tests and resistant to behavioral despair in the forced swim test. These mice displayed more home-cage voluntary wheel running activities, rearings in a large arena and open-arm visits in an elevated plus maze. Treatments with valproate and olanzapine, but not lithium reduced baseline activities in ERK1-ablated mice. All three treatments attenuated amphetamine-induced hyperactivity in ablated mice. These data indicate a profound involvement of ERK1 signaling in behavioral excitement and in the behavioral action of antimanic agents. The extent to which ERK pathway perturbation contributes to the susceptibility, mood switch mechanism(s) and symptom pathophysiology of bipolar disorder requires further investigation. Whether there is a shared mechanism through which mood stabilizers produce their clinical actions on mood, thought and behavioral symptoms of mania also requires further investigation.