Ubiquitin ligase TRIM3 controls hippocampal plasticity and learning by regulating synaptic gamma-actin levels

Synaptic plasticity requires remodeling of the actin cytoskeleton. Although two actin isoforms, beta- and gamma-actin, are expressed in dendritic spines, the specific contribution of gamma-actin in the expression of synaptic plasticity is unknown. We show that synaptic gamma-actin levels are regulated by the E3 ubiquitin ligase TRIM3. TRIM3 protein and Actg 1 transcript are co-localized in messenger ribonucleoprotein granules responsible for the dendritic targeting of messenger RNAs. TRIM3 polyubiquitylates gamma-actin, most likely cotranslationally at synaptic sites. Trim3(-1-) mice consequently have increased levels of gamma-actin at hippocannpal synapses, resulting in higher spine densities, increased long-term potentiation, and enhanced short-term contextual fear memory consolidation. Interestingly, hippocampal deletion of Actg 1 caused an increase in long-term fear memory. Collectively, our findings suggest that temporal control of gamma-actin levels by TRIM3 is required to regulate the timing of hippocampal plasticity. We propose a model in which TRIM3 regulates synaptic gamma-actin turnover and actin filament stability and thus forms a transient inhibitory constraint on the expression of hippocampal synaptic plasticity.