Biou Virginie, Brinkhaus Heike, Malenka Robert C, Matus Andrew
Friedrich Miescher Institute, Basel, Switzerland.
Eur J Neurosci. 2008 Jun;27(11):2847-59. doi: 10.1111/j.1460-9568.2008.06269.x.
Dendritic spines are major sites of morphological plasticity in the CNS, but the molecular mechanisms that regulate their dynamics remain poorly understood. Here we show that the association of drebrin with actin filaments plays a major role in regulating dendritic spine stability and plasticity. Overexpressing drebrin or the internal actin-binding site of drebrin in rat hippocampal neurons destabilized mature dendritic spines so that they lost synaptic contacts and came to resemble immature dendritic filopodia. Drebrin-induced spine destabilization was dependent on Ras activation: expression of constitutively active Ras destabilized spine morphology whereas drebrin-induced spine destabilization was rescued by co-expressing dominant negative Ras. Conversely, RNAi-mediated drebrin knockdown prevented Ras-induced destabilization and promoted spine maturation in developing neurons. Together these data demonstrate a novel mechanism in which the balance between stability and plasticity in dendritic spines depends on binding of drebrin to actin filaments in a manner that is regulated by Ras.
树突棘是中枢神经系统中形态可塑性的主要位点，但调节其动态变化的分子机制仍知之甚少。在此我们表明，drebrin与肌动蛋白丝的结合在调节树突棘稳定性和可塑性方面发挥着主要作用。在大鼠海马神经元中过表达drebrin或drebrin的内部肌动蛋白结合位点会使成熟树突棘不稳定，使其失去突触联系并变得类似于未成熟的树突丝状伪足。drebrin诱导的树突棘不稳定依赖于Ras激活：组成型活性Ras的表达会使树突棘形态不稳定，而共表达显性负性Ras可挽救drebrin诱导的树突棘不稳定。相反，RNA干扰介导的drebrin敲低可防止Ras诱导的不稳定，并促进发育中神经元的树突棘成熟。这些数据共同证明了一种新机制，即树突棘稳定性和可塑性之间的平衡取决于drebrin以受Ras调节的方式与肌动蛋白丝的结合。
