Drug abuse signaling pathways that regulate CREB mRNA translation in dendrites

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DESCRIPTION (provided by applicant): The objective of the proposed research is to understand how synaptic stimulation by drugs of abuse leads to transcriptional effects in the nucleus. All drugs of abuse have been shown to stimulate changes in gene expression. These changes are thought to underlie many of the long-term changes seen following repeated drug exposure that characterize addiction. However, it is unclear how signaling at a synapse could affect gene transcription in the nucleus, which can be separated by a distance of several hundred micrometers. We have recently discovered that the mRNA encoding CREB, a transcription factor, is present in the axons and growth cones of developing neurons, and this mRNA is translated 'locally' upon exposure to NGF, resulting in the accumulation of CREB in growth cones, which is then phosphorylated and retrogradely trafficked to the nucleus. This axonally-derived CREB binds to promoter sequences and stimulates the gene transcription necessary for neuronal survival. Thus, local translation and retrograde trafficking is required for growth cone- to-nucleus signaling. In addition to its role in neuronal survival, CREB has critical roles in mediating the long- term changes associated with drugs of abuse. Our preliminary data show that CREB is translated within dendrites. In this application, we propose experiments to identify drug abuse-related synaptic signaling pathways that regulate dendritic CREB translation, phosphorylation, and nuclear translocation. Furthermore, using neurons selectively-deficient in dendritic CREB mRNA, we will determine the role of dendritic CREB mRNA in nuclear gene transcription. Together, the experiments in this CEBRA application will explore the role of this unanticipated mode of signaling which would significantly impact our current thinking about the molecular mechanisms employed by drugs of abuse.