ANTISENSE OLIGODEOXYNUCLEOTIDE-MEDIATED DISRUPTION OF HIPPOCAMPAL CAMP RESPONSE ELEMENT-BINDING PROTEIN-LEVELS IMPAIRS CONSOLIDATION OF MEMORY FOR WATER MAZE TRAINING

Extensive evidence suggests that long term memory (LTM) formation is d ependent on the activation of neuronal second messenger systems and re quires protein synthesis, The cAMP response element binding protein (C REB) is a constitutively expressed regulatory transcription factor tha t couples changes in second messenger levels to changes in cellular tr anscription, Several recent studies suggest that CREB and related tran scription factors regulate gene expression necessary for neuronal plas ticity and LTM, However, the role of CREE, within defined mammalian br ain structures, in mediating the cellular events underlying LTM format ion has not been investigated, We examined whether CREB-mediated trans cription within the dorsal hippocampus is critical to LTM consolidatio n of water maze spatial training, which is known to depend on dorsal h ippocampal function, Pretraining infusions of antisense oligodeoxynucl eotides (ODN) directed against CREB mRNA were used to disrupt hippocam pal CREB protein levels in adult rats, Control groups received pretrai ning infusions of ODN of the same base composition but in a randomized order (scrambled ODN) or buffer, Task acquisition and memory up to 4 h (i.e., short term memory) were similar in CREB antisense ODN and con trol groups, In contrast, CREB antisense ODN-infused rats exhibited si gnificantly impaired memory 48 h later (i.e., LTM), Moreover, administ ration of antisense ODN 1 day after training did not affect subsequent retention performance, These findings provide the first evidence that CREB-mediated transcription is integral to hippocampal-dependent memo ry consolidation processes.