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TRIM3 regulates synaptic γ-actin levels. TRIM3-deficient mice consequently have higher hippocampal spine densities, increased long-term potentiation, and enhanced contextual fear memory consolidation, indicating that temporal control of ACTG1 levels by TRIM3 is required to constrain hippocampal plasticity within physiological boundaries., Synaptic plasticity requires remodeling of the actin cytoskeleton. Although two actin isoforms, β- and γ-actin, are expressed in dendritic spines, the specific contribution of γ-actin in the expression of synaptic plasticity is unknown. We show that synaptic γ-actin levels are regulated by the E3 ubiquitin ligase TRIM3. TRIM3 protein and Actg1 transcript are colocalized in messenger ribonucleoprotein granules responsible for the dendritic targeting of messenger RNAs. TRIM3 polyubiquitylates γ-actin, most likely cotranslationally at synaptic sites. Trim3−/− mice consequently have increased levels of γ-actin at hippocampal synapses, resulting in higher spine densities, increased long-term potentiation, and enhanced short-term contextual fear memory consolidation. Interestingly, hippocampal deletion of Actg1 caused an increase in long-term fear memory. Collectively, our findings suggest that temporal control of γ-actin levels by TRIM3 is required to regulate the timing of hippocampal plasticity. We propose a model in which TRIM3 regulates synaptic γ-actin turnover and actin filament stability and thus forms a transient inhibitory constraint on the expression of hippocampal synaptic plasticity.

KIF21B, a kinesin family (KIF) protein, is a plus end-directed microtubule motor. The KIF21B gene is highly expressed in neuronal tissue and spleen and is a susceptibility locus for multiple sclerosis. KIF21B motility is regulated through TRIM3, a member of the cytoskeleton-associated-recycling or transport (CART) complex, involved in vesicular receptor recycling. Here we show that the GABAA receptor γ2-subunit co-precipitates and co-localizes with KIF21B in cultured hippocampal neurons. Knockdown of KIF21B gene expression through small hairpin (sh) RNA reduces the number of γ2-subunit-containing GABAA receptor (GABAARs) clusters in neurites and at the cell surface. Our data suggest that KIF21B participates in the delivery of GABAAR transport vesicles into dendrites.