The ubiquitin proteasome system functions as an inhibitory constraint on synaptic strengthening

Background: Long-lasting forms of synaptic plasticity have been shown to depend on changes in gene expression. Although many studies have focused on the regulation of transcription and translation during learning-related synaptic plasticity, regulated protein degradation provides another common means of altering the macromolecular composition of cells. Results: We have investigated the role of the ubiquitin proteasome system in long-lasting forms of learning-related plasticity in Aplysia sensory-motor synapses. We find that inhibition of the proteasome produces a long-lasting (24 hr) increase in synaptic strength between sensory and motor neurons and that it dramatically enhances serotonin-induced long-term facilitation. The increase in synaptic strength produced by proteasome inhibitors is dependent on translation but not transcription. In addition to the increase in synaptic strength, proteasome inhibition leads to an increase in the number of synaptic contacts formed between the sensory and motor neurons. Blockade of the proteasome in isolated postsynaptic motor neurons produces an increase in the glutamate-evoked postsynaptic potential, and blockade of the proteasome in the isolated presynaptic sensory cells produces increases in neurite length and branching. Conclusions: We conclude that both pre- and postsynaptic substrates of the ubiquitin proteasome function constitutively to regulate synaptic strength and growth and that the ubiquitin proteasome pathway functions in mature neurons as an inhibitory constraint on synaptic strengthening.