Phosphorylated cAMP response element-binding protein as a molecular markerof memory processing in rat hippocampus: Effect of novelty

From mollusks to mammals the activation of cAMP response element-binding pr otein (CREB) appears to be an important step in the formation of long-term memory (LTM). Here we show that a 5 min exposure to a novel environment (op en field) 1 hr after acquisition of a one-trial inhibitory avoidance traini ng hinders both the formation of LTM for the avoidance task and the increas e in the phosphorylation state of hippocampal Ser 133 CREB [phosphorylated CREB (pCREB)] associated with the avoidance training. To determine whether this LTM deficit is attributable to the reduced pCREB level, rats were bila terally cannulated to deliver Sp-adenosine 3',5'-cyclic monophosphothioate (Sp-cAMPS), an activator of PKA. Infusion of Sp-Adenosine 3',5'-cyclic mono phosphothioate Sp-cAMPS to CA1 region increased hippocampal pCREB levels an d restored normal LTM of avoidance learning in rats exposed to novelty. Mor eover, a 5 min exposure to the open field 10 min before the avoidance train ing interferes with the amnesic effect of a second 5 min exposure to the op en field 1 hr after avoidance training and restores the hippocampal levels of pCREB. In contrast, the avoidance training-associated activation of extr acellular signal-regulated kinases (p42 and p44 mitogen-activated protein k inases) in the hippocampus is not altered by novelty. Together, these findi ngs suggest that novelty regulates LTM formation by modulating the phosphor ylation state of CREB in the hippocampus.