The kinesin Kif21b binds myosin Va and mediates changes in actin dynamics underlying homeostatic synaptic downscaling

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. [Display omitted] •Kif21b localization in dendritic spines depends on myosin Va and synaptic activity•Knockout of Kif21b gene expression alters actin dynamics in dendritic spines•Kif21b associates with GKAP underlying homeostatic synaptic downscaling (HSP)•Adaptation of actin turnover in spines after HSP induction requires Kif21b/MyoVa Gromova et al. show that the kinesin motor protein Kif21b mediates non-canonical functions at the actin cytoskeleton by (1) interacting with myosin Va, (2) entering dendritic spines, and (3) changing actin dynamics in spines. The authors functionally link Kif21b-modulated actin dynamics to GKAP-mediated homeostatic synaptic plasticity.