Neuronal plasticity is thought to underlie a variety of behavioral processes, including memory formation and addiction. Long-term potentiation (LTP) is a persistent, use-dependent form of neuronal plasticity exhibited by synapses in the hippocampus, a brain structure that has been implicated in memory formation and retrieval. Hippocampal LTP has emerged as the major model system for studying the cellular basis of behavioral memory. Long-lasting forms of LTP require protein synthesis (translation). However, little is known about the relationship between LTP and the regulation of translation. The experiments of this proposal address this issue by determining the role in LTP of several important translation control points, which are regulated through protein phosphorylation. We will use synaptic stimulation to induce persistent LTP in rat hippocampal slices. These slices will then be analyzed with biochemical and immunohistochemical methods to determine the distribution and phosphorylation of proteins that participate in translation initiation. Experiments will test for the activation of ribosomal S6 kinase and the phosphorylation of S6, a protein of the 40S ribosomal subunit that selectively promotes the translation of mRNAs containing a terminal oligopyrimidine (TOP) tract in their 5' untranslated regions. Other studies will investigate the possible involvement of the translation initiation factor elF4E and its regulatory binding partner, 4E-BP, which preferentially regulate the translation of transcripts containing structured 5' ends. The cellular mechanisms underlying the regulation of these initiation factors will be studied by inhibiting enzymes of the translation initiation pathway as well as more upstream signaling pathways. Finally, a set of immunohistochemical experiments will study the distribution of translation-related phosphoproteins in the dendritic region using quantitative confocal microscopy. The results of this proposal will shed light on the mechanisms that participate in drug addiction, as well as learning and memory, by providing new information on the role of translation control in neuronal plasticity.
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