Antisense DNA against calcineurin facilitates memory in contextual fear conditioning by lowering the threshold for hippocampal long-term potentiation induction.

In the previous study, we demonstrated that the antisense oligodeoxynucleotides against calcineurin Aalpha and Abeta, catalytic subunits of Ca(2+)/calmodulin-dependent protein phosphatase, produce a facilitatory effect on long-term potentiation induction in the hippocampal CA1 region in rats anesthetized with urethane. Here, we have studied how animals, in which the hippocampal long-term potentiation induction is enhanced by antisense oligodeoxynucleotides against calcineurin, perform in learning tasks that depend on hippocampal function. The rats received antisense oligodeoxynucleotides by bilateral ventricular administration via miniosmotic pumps. We tested four groups of rats, three infused with either antisense oligodeoxynucleotides, scramble oligodeoxynucleotides, or saline, and untreated rats, for two types of hippocampus-dependent learning, water maze and contextual fear conditioning. After the behavioral tests, we conducted a long-term potentiation induction test to determine whether long-term potentiation induction was enhanced. In contextual fear conditioning, rats in which long-term potentiation induction was enhanced by antisense oligodeoxynucleotides displayed significantly more conditioned freezing response than control rats. Rats with enhanced long-term potentiation induction showed no differences in shock sensitivity, general activity, or light-dark choice from control rats. In contrast with contextual fear conditioning, rats with enhanced long-term potentiation induction showed no difference in spatial learning performance on the water maze compared with control rats. These results demonstrate that an enhancement in long-term potentiation induction produced by the inhibition of calcineurin leads to an increase in memory strength in specific forms of hippocampus-dependent learning.