Program in Neuroscience and Behavioral Disorders, Duke-National University of Singapore Medical School, Singapore.
Psychiatry Clin Neurosci. 2019 Sep;73(9):541-550. doi: 10.1111/pcn.12899. Epub 2019 Jul 8.
Dendritic spines are tiny postsynaptic protrusions from a dendrite that receive most of the excitatory synaptic input in the brain. Functional and structural changes in dendritic spines are critical for synaptic plasticity, a cellular model of learning and memory. Conversely, altered spine morphology and plasticity are common hallmarks of human neurodevelopmental disorders, such as intellectual disability and autism. The advances in molecular and optical techniques have allowed for exploration of dynamic changes in structure and signal transduction at single-spine resolution, providing significant insights into the molecular regulation underlying spine structural plasticity. Here, I review recent findings on: how synaptic stimulation leads to diverse forms of spine structural plasticity; how the associated biochemical signals are initiated and transmitted into neuronal compartments; and how disruption of single genes associated with neurodevelopmental disorders can lead to abnormal spine structure in human and mouse brains. In particular, I discuss the functions of the Ras superfamily of small GTPases in spatiotemporal regulation of the actin cytoskeleton and protein synthesis in dendritic spines. Multiple lines of evidence implicate disrupted Ras signaling pathways in the spine structural abnormalities observed in neurodevelopmental disorders. Both deficient and excessive Ras activities lead to disrupted spine structure and deficits in learning and memory. Dysregulation of spine Ras signaling, therefore, may play a key role in the pathogenesis of multiple neurodevelopmental disorders with distinct etiologies.
树突棘是树突上的微小突起，接收大脑中大部分兴奋性突触输入。树突棘的功能和结构变化对于突触可塑性至关重要，突触可塑性是学习和记忆的细胞模型。相反，树突棘形态和可塑性的改变是人类神经发育障碍的共同特征，如智力障碍和自闭症。分子和光学技术的进步使得能够在单个树突棘分辨率下探索结构和信号转导的动态变化，为树突棘结构可塑性的分子调控提供了重要的见解。在这里，我回顾了最近的发现：突触刺激如何导致多种形式的树突棘结构可塑性；相关生化信号如何被引发并传递到神经元隔室；以及与神经发育障碍相关的单个基因突变如何导致人类和老鼠大脑中的异常树突棘结构。特别是，我讨论了 Ras 家族小 GTPases 在树突棘中肌动蛋白细胞骨架和蛋白质合成的时空调节中的作用。有多项证据表明，Ras 信号通路的破坏与神经发育障碍中观察到的脊柱结构异常有关。Ras 活性不足和过度都会导致脊柱结构破坏以及学习和记忆缺陷。因此，脊柱 Ras 信号转导的失调可能在具有不同病因的多种神经发育障碍的发病机制中发挥关键作用。
