Department of Psychiatry and Behavioral Sciences, Stanford University, CA 94305.
Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030.
eNeuro. 2021 Jul 6;8(4). doi: 10.1523/ENEURO.0056-21.2021. Print 2021 Jul-Aug.
The inflexible repetitive behaviors and "insistence on sameness" seen in autism imply a defect in neural processes controlling the balance between stability and plasticity of synaptic connections in the brain. It has been proposed that abnormalities in the Ras-ERK/MAPK pathway, a key plasticity-related cell signaling pathway known to drive consolidation of clustered synaptic connections, underlie altered learning phenotypes in autism. However, a link between altered Ras-ERK signaling and clustered dendritic spine plasticity has yet to be explored in an autism animal model The formation and stabilization of dendritic spine clusters is abnormally increased in the MECP2-duplication syndrome mouse model of syndromic autism, suggesting that ERK signaling may be increased. Here, we show that the Ras-ERK pathway is indeed hyperactive following motor training in MECP2-duplication mouse motor cortex. Pharmacological inhibition of ERK signaling normalizes the excessive clustered spine stabilization and enhanced motor learning behavior in MECP2-duplication mice. We conclude that hyperactive ERK signaling may contribute to abnormal clustered dendritic spine consolidation and motor learning in this model of syndromic autism.
自闭症中观察到的刻板重复行为和“坚持一致性”表明，控制大脑中突触连接稳定性和可塑性之间平衡的神经过程存在缺陷。有人提出， Ras-ERK/MAPK 通路异常，这是一种已知可驱动簇状突触连接巩固的关键可塑性相关细胞信号通路，是自闭症中改变学习表型的基础。然而， Ras-ERK 信号转导与簇状树突棘可塑性之间的联系尚未在自闭症动物模型中得到探索。在自闭症综合征的 MECP2 重复综合征小鼠模型中，树突棘簇的形成和稳定异常增加，表明 ERK 信号可能增加。在这里，我们表明 Ras-ERK 通路在 MECP2 重复小鼠运动皮层的运动训练后确实过度活跃。ERK 信号转导的药理学抑制可使 MECP2 重复小鼠中过度簇状棘稳定和增强的运动学习行为正常化。我们得出结论，过度活跃的 ERK 信号可能导致该综合征自闭症模型中异常的簇状树突棘巩固和运动学习。
