SPACED TRAINING INDUCES NORMAL LONG-TERM-MEMORY IN CREB MUTANT MICE

Background: The cAMP responsive element binding protein (CREB) is a tr anscription factor the activity of which is modulated by increases in the intracellular levels of cAMP and calcium. Results from studies wit h Aplysia, Drosophila and mice indicate that CREB-activated transcript ion is required for long-term memory. Furthermore, a recent study foun d that long-term memory for olfactory conditioning can be induced with a single trial in transgenic Drosophila expressing a CREB activator, whereas in normal flies, with presumably lower CREB-mediated transcrip tion levels, conditioning requires multiple spaced trials. This sugges ts that CREB-mediated transcription is important in determining the ty pe of training required for long-term memory of olfactory conditioning in Drosophila. Interestingly, studies with cultured Aplysia neurons i ndicated that removing a CREB repressor promoted the formation of long -term facilitation, a cellular model of non-associative memory, Result s: Here, we have confirmed that mice lacking the alpha and Delta CREB proteins (CREB(alpha Delta-)) have abnormal long-term, but not short-t erm, memory, as tested in an ethologically meaningful task. Importantl y, additional spaced training can overcome the profound memory deficit s of CREB(alpha Delta-) mutants. Increasing the intertrial interval fr om 1 to 60 minutes overcame the memory deficits of the CREB(alpha Delt a-) mice in three distinct behavioral tasks: contextual fear condition ing, spatial learning and socially transmitted food preferences. Concl usions: Previous findings and results presented here demonstrate that CREB mutant mice have profound long-term memory deficits. Importantly, our findings indicate that manipulations of CREB function can affect the number of trials and the intertrial interval required for committi ng information to long-term memory. Remarkably, this effect of CREB fu nction is not restricted to simple conditioning tasks, but also affect s complex behaviors such as spatial memory and memory for socially tra nsmitted food preferences.