Elucidation of mechanisms underlying synaptic plasticity is likely to aid in understanding both normal and abnormal functions of the nervous system. A tractable model system for investigating synaptic plasticity is long-term presynaptic facilitation of sensory-to-motor neuron synapses in Aplysia, the cellular mechanism underlying a simple form of learning and memory. The overall goal of this proposal is to investigate how the ubiquitin-proteasome pathway contributes to long-term facilitation. Long-term facilitation requires signal transduction from the neurotransmitter 5-HT to the nucleus for activation of gene transcription by the cAMP-responsive element binding protein (CREB). Normally, gene transcription by CREB is inhibited by repressers. Previous studies revealed that in Aplysia neurons, the CREB represser CREBIb is degraded by the ubiquitin-proteasome pathway. Preliminary results indicate that CREBIb is phosphorylated by protein kinase C.
The first aim i s to investigate regulation of CREBIb ubiquitination by phosphorylation and to show that phosphorylation-mediated regulation of CREBIb ubiquitination and degradation is critical for induction of long-term facilitation. During induction of long-term facilitation, regulation of proteasome is likely to play a critical role as well. Preliminary data show that the proteasome activity in the synaptic terminals significantly differs from the proteasome activity in the nucleus.
The second aim i s to test the hypothesis that the proteasome is differentially regulated in the nucleus and in the synaptic terminals. These studies are likely to provide insights into the mechanisms by which precise spatial and temporal regulation of ubiquitin-proteasome-mediated proteolysis contribute to long-term synaptic plasticity. Relevance: Memory that lasts a long-period of time forms only with strong or repeated stimulation of the senses. A key protein that suppresses memory formation needs to be degraded before long-lasting memory can form. The suppressor protein is marked for degradation by attachment of a tag called ubiquitin and is degraded by a part of the cell named the proteasome. The protein degradation is abnormal in many brain diseases like Alzheimer's. This research could shed light on how impairment in protein degradation could lead to memory loss as well as brain diseases. ? ?
