Posttranscriptional regulation of gene expression in learning by the neuronal ELAV-like mRNA-stabilizing proteins

The view that memory is encoded by variations in the strength of synapses i mplies that long-term biochemical changes take place within subcellular mic rodomains of neurons. These changes are thought ultimately to be an effect of transcriptional regulation of specific genes. Localized changes, however , cannot be fully explained by a purely transcriptional control of gene exp ression. The neuron-specific ELAV-like HuB, HuC, and HuD RNA-binding protei ns act posttranscriptionally by binding to adenine- and uridine-rich elemen ts (ARES) in the 3 ' untranslated region of a set of target mRNAs, and by i ncreasing mRNA cytoplasmic stability and/or rate of translation. Here we sh ow that neuronal ELAV-like genes undergo a sustained up-regulation in hippo campal pyramidal cells only of mice and rats that have learned a spatial di scrimination paradigm. This learning-specific increase of ELAV-like protein s was localized within cytoplasmic compartments of the somata and proximal dendrites and was associated with the cytoskeleton. This increase was also accompanied by enhanced expression of the GAP-43 gene, known to be regulate d mainly posttranscriptionally and whose mRNA is demonstrated here to be an in vivo ELAV-like target. Antisense-mediated knockdown of HuC impaired spa tial learning performance in mice and induced a concomitant downregulation of GAP-43 expression. Neuronal ELAV-like proteins could exert learning-indu ced posttranscriptional control of an array of target genes uniquely suited to subserve substrates of memory storage.