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Schreiber et al. reveal that a ubiquitin ligase regulates synaptic plasticity and memory formation by targeting γ-actin for degradation.
The ubiquitin ligase TRIM3 localizes to the dendrites and synapses of hippocampal neurons, but its function in the brain remains unclear. Schreiber et al. found that mice lacking TRIM3 learned to anticipate electric shocks quicker than wild-type animals. Accordingly, TRIM3-deficient hippocampal neurons had a higher density of dendritic spines and showed increased long-term potentiation, a type of synaptic plasticity associated with learning and memory.
TRIM3 has been proposed to target several synaptic proteins for degradation, but the levels of these candidate substrates were unaltered in TRIM3-knockout mice. Schreiber et al. therefore looked for alternative TRIM3 targets and found that the enzyme can polyubiquitylate γ-actin (probably cotranslationally, because TRIM3 localizes to synaptic ribonucleoprotein particles containing γ-actin–encoding mRNAs). Synaptic γ-actin levels were consequently increased in the absence of TRIM3, the researchers discovered. Although this was associated with enhanced memory consolidation over shorter time periods, depleting γ-actin from hippocampal neurons enhanced mice’s long-term memory of electric shocks, suggesting that the temporal regulation of γ-actin levels by TRIM3 is critical for the appropriate timing of synaptic plasticity.
γ-Actin is almost identical to β-actin, but its incorporation into actin filaments increases their stability in vitro. Author Ronald van Kesteren says that it will be important to investigate how γ-actin levels influence actin stability and synapse morphology in vivo.