Department of Molecular Neurogenetics, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
Department of Molecular Neurogenetics, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
Cell Rep. 2023 Jul 25;42(7):112743. doi: 10.1016/j.celrep.2023.112743. Epub 2023 Jul 6.
Homeostatic synaptic plasticity adjusts the strength of synapses to restrain neuronal activity within a physiological range. Postsynaptic guanylate kinase-associated protein (GKAP) controls the bidirectional synaptic scaling of AMPA receptors (AMPARs); however, mechanisms by which chronic activity triggers cytoskeletal remodeling to downscale synaptic transmission are barely understood. Here, we report that the microtubule-dependent kinesin motor Kif21b binds GKAP and likewise is located in dendritic spines in a myosin Va- and neuronal-activity-dependent manner. Kif21b depletion unexpectedly alters actin dynamics in spines, and adaptation of actin turnover following chronic activity is lost in Kif21b-knockout neurons. Consistent with a role of the kinesin in regulating actin dynamics, Kif21b overexpression promotes actin polymerization. Moreover, Kif21b controls GKAP removal from spines and the decrease of GluA2-containing AMPARs from the neuronal surface, thereby inducing homeostatic synaptic downscaling. Our data highlight a critical role of Kif21b at the synaptic actin cytoskeleton underlying homeostatic scaling of neuronal firing.
稳态突触可塑性调节突触强度，将神经元活动限制在生理范围内。突触后鸟苷酸激酶相关蛋白（GKAP）控制 AMPA 受体（AMPAR）的双向突触缩放；然而，慢性活动触发细胞骨架重塑以降低突触传递的机制还知之甚少。在这里，我们报告说微管依赖性驱动蛋白 Kif21b 与 GKAP 结合，并且同样以肌球蛋白 Va 和神经元活性依赖性的方式存在于树突棘中。出人意料的是，Kif21b 耗竭会改变棘突中的肌动蛋白动力学，并且在 Kif21b 敲除神经元中，慢性活动后的肌动蛋白周转率适应性丧失。与驱动蛋白在调节肌动蛋白动力学中的作用一致，Kif21b 过表达促进肌动蛋白聚合。此外，Kif21b 控制 GKAP 从棘突中的去除以及 GluA2 包含的 AMPAR 从神经元表面的减少，从而诱导稳态突触缩放。我们的数据强调了 Kif21b 在突触肌动蛋白细胞骨架中的关键作用，该骨架是神经元放电的稳态缩放的基础。
