State-dependent diffusion of actin-depolymerizing factor/cofilin underlies the enlargement and shrinkage of dendritic spines.
State-dependent diffusion of actin-depolymerizing factor/cofilin underlies the enlargement and shrinkage of dendritic spines.
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DOI：
10.1038/srep32897
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发表时间：
2016-09-06
影响因子：
4.6
通讯作者：
Kasai H
中科院分区：
文献类型：
--
作者：
Noguchi J;Hayama T;Watanabe S;Ucar H;Yagishita S;Takahashi N;Kasai H
树突棘是大脑中大多数兴奋性突触的突触后部位，棘的增大和收缩分别引起突触的长时程增强和抑制。由于脊柱结构的可塑性伴随着肌动蛋白支架的重塑，我们假设丝状肌动蛋白调节蛋白cofilin在这一过程中起着至关重要的作用。在这里，我们研究了cofilin的扩散特性，肌动蛋白切断和解聚的行动，其中激活去磷酸化。使用荧光标记的Cofilin融合蛋白和双光子成像测量Cofilin扩散。我们发现，cofilins是高度扩散沿着树突在休息状态。然而，在脊柱扩大，野生型cofilin和拟磷酸化cofilin突变体仍然局限于刺激的脊柱，而nonphosphorylatable突变体不。此外，用竞争性肽抑制cofilin磷酸化使棘增大失效，表明磷酸化cofilin积累是增大的关键调节因子，其定位于单个棘。相反，脊柱收缩会扩散到相邻的脊柱，即使是由比扩大更弱的刺激触发的。注射到锥体神经元索马体中的外源性cofilin的扩散导致脊柱收缩和脊柱中的PSD 95降低，这表明去磷酸化的内源性cofilin的扩散是脊柱收缩和长期抑郁的扩散的基础。
Dendritic spines are the postsynaptic sites of most excitatory synapses in the brain, and spine enlargement and shrinkage give rise to long-term potentiation and depression of synapses, respectively. Because spine structural plasticity is accompanied by remodeling of actin scaffolds, we hypothesized that the filamentous actin regulatory protein cofilin plays a crucial role in this process. Here we investigated the diffusional properties of cofilin, the actin-severing and depolymerizing actions of which are activated by dephosphorylation. Cofilin diffusion was measured using fluorescently labeled cofilin fusion proteins and two-photon imaging. We show that cofilins are highly diffusible along dendrites in the resting state. However, during spine enlargement, wild-type cofilin and a phosphomimetic cofilin mutant remain confined to the stimulated spine, whereas a nonphosphorylatable mutant does not. Moreover, inhibition of cofilin phosphorylation with a competitive peptide disables spine enlargement, suggesting that phosphorylated-cofilin accumulation is a key regulator of enlargement, which is localized to individual spines. Conversely, spine shrinkage spreads to neighboring spines, even though triggered by weaker stimuli than enlargement. Diffusion of exogenous cofilin injected into a pyramidal neuron soma causes spine shrinkage and reduced PSD95 in spines, suggesting that diffusion of dephosphorylated endogenous cofilin underlies the spreading of spine shrinkage and long-term depression.
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