Localization of Fascin to Dendritic Protrusions Regulates Postsynaptic Plasticity.

The Fascin family of actin-bundling proteins organizes actin filaments (F-actin) into tightly packed bundles that drive dynamic membrane protrusions such as filopodia. In neurons, fascin has been thought to primarily function in axons, as previous studies reported its absence from dendritic filopodia and spines. Here, we demonstrate that fascin is both present and functionally important in dendritic compartments. Using optimized immunocytochemistry and CRISPR-based endogenous tagging of fascin1 in cultured hippocampal neurons, we show that fascin localizes to developing dendritic filopodia and is enriched in mature dendritic spines. Super-resolution imaging further reveals that fascin is organized into discrete nanoscale foci within spine heads, but not the spine neck. Finally, we show that CRISPR-mediated knockout of fascin1 in mature hippocampal neurons impairs synaptic potentiation, without affecting baseline excitatory synaptic transmission. Together, our findings uncover a previously overlooked aspect of actin organization in dendritic spines and establish fascin as a critical regulator of postsynaptic plasticity. Summary Statement: The actin bundling protein fascin localizes to dendritic filopodia and spines, where it regulates activity-dependent synaptic plasticity.