In the short-term, a single neuron receiving multiple excitatory and inhibitory inputs at spatially distinct locales will sum all of them into the decision of whether or not to fire a nerve impulse. Guan et al. investigated the mechanisms whereby neurons integrate facilitatory and inhibitory inputs leading to long-term changes in synaptic function. In various systems, long-term facilitation of synaptic efficacy involves activation of the transcription factor cyclic adenosine monophosphate response element binding protein-1 (CREB1), relief of CREB2-mediated transcriptional repression, and induction of CREB1-sensitive genes including CAAT box enhancer-binding protein (C/EBP). Using cultured Aplysia sensory neurons with bifurcating axons that make synapses with distinct target motor neurons, the authors found that long-term depression of synaptic function, elicited by repeated local applications of the peptide FMRFamide (FMRFa), was blocked after injection of antibodies to CREB2. Although short-term facilitation (in response to a single application of 5-hydroxytryptamine, 5-HT) and short-depression (in response to FMRFa) elicited at different synapses were independent of one another, long-term depression elicited at one set of synapses overrode long-term facilitation elicited at a second set. Using RT-PCR, the authors showed that FMRFa blocked a 5-HT-dependent increase in C/EBP mRNA. Chromatin immunoprecipitation assays indicated that 5-HT treatment led to recruitment of CREB binding protein, a histone acetylase, to the C/EBP promoter, concurrent with histone acetylation, whereas FMRFa treatment led to CREB2 and histone deacetylase recruitment and histone deacetylation. The effects of FMRFa persisted after combined treatment with 5-HT, just as the physiological effects of FMRFa overrode those of 5-HT. Z. Guan, M. Giustetto, S. Lomvardas, J.-H. Kim, M. C. Miniaci, J. H. Schwartz, D. Thanos, E. R. Kandel, Integration of long-term-memory-related synaptic plasticity involves bidirectional regulation of gene expression and chromatin structure. Cell 111 , 483-493 (2002). [Online Journal]