Genomic Approaches to Identifying Transcriptional Targets of AP-1, CREB and JNK Signaling in the Nervous System of Drosophila melanogaster

by Etter, Paul Dezso.

Although a few regulators of memory and addiction have been identified, the biochemical pathways that mediate the development of addiction and memory remain poorly understood. In addition, important questions remain as to how these two phenomena can persist for so long, sometimes for the entire life of an individual. Signaling molecules and transcription factors are activated in response to stimuli that induce long-term neuronal plastic changes. The transcription factor CREB (cAMPresponsive element binding protein) is clearly involved in triggering processes of addiction and memory, but its sustained activation following a course of chronic drug exposure (or learning) returns to baseline within days [1]. Even the enduring increased levels of ?FosB (a Fos family transcription factor that couples with other proteins in the AP-1 family to form transcriptional activator/repressor complexes) observed in regions of the mammalian brain following chronic drug exposure, persists for only weeks or months. Thus, although CREB and ?FosB probably initiate the very stable behavioral changes seen with addiction and memory, their alterations cannot mediate those behavioral changes per se [1]. Long-term up- or down-regulation of molecules downstream of these transcription factors, or others, must be responsible for the enduring modifications in synaptic connectivity and structure believed to be required for the maintenance of these durable behavioral states [2]. Many believe that more rapid progress will be made toward understanding the molecular basis of addiction if research efforts proceed hand-in-hand with, rather than in 12 isolation from, the overlapping neurobiological study of learning and memory [1, 2]. The importance and utility of using simple model systems such as Drosophila and Aplysia to identify and characterize genes involved in long-term synaptic plasticity, and hence memory formation, is well documented [3-5]. Identification and functional analyses of neuronal genes transcriptionally regulated by AP-1 and CREB in Drosophila would elaborate on molecular mechanisms of long-term plasticity and hence help us understand, and perhaps manipulate, processes that underlie addiction and memory. 13