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Memory deficits in aging affect millions of people and are often disturbing to those concerned. Dissection of the molecular control of learning and memory is paramount to understand and possibly enhance cognitive functions. Old-age memory loss also has been recently linked to altered Ca(2+) homeostasis. We have previously identified DREAM (downstream regulatory element antagonistic modulator), a member of the neuronal Ca(2+) sensor superfamily of EF-hand proteins, with specific roles in different cell compartments. In the nucleus, DREAM is a Ca(2+)-dependent transcriptional repressor, binding to specific DNA signatures, or interacting with nucleoproteins regulating their transcriptional properties. Also, we and others have shown that dream mutant (dream(-/-)) mice exhibit marked analgesia. Here we report that dream(-/-) mice exhibit markedly enhanced learning and synaptic plasticity related to improved cognition. Mechanistically, DREAM functions as a negative regulator of the key memory factor CREB in a Ca(2+)-dependent manner, and loss of DREAM facilitates CREB-dependent transcription during learning. Intriguingly, 18-month-old dream(-/-) mice display learning and memory capacities similar to young mice. Moreover, loss of DREAM protects from brain degeneration in aging. These data identify the Ca(2+)-regulated "pain gene" DREAM as a novel key regulator of memory and brain aging.

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In this paper, we reported evidence that a protein variously called DREAM/Calsenilin/KChip3 controls learning and memory in mice. It has been brought to our attention that the antibody against DREAM (FL-214, Santa Cruz sc-9142, lot #B230) that we used for expression analyses in genetically confirmed knockout mice (Figure 3B), as a specificity control in studies of DREAM-DNA binding (Figure 3A, lane 1), and for DREAM-CREB-CBP interactions (Figure 3C, lanes 4, 9, and 14) might on western blots also detect other proteins related to DREAM/Calsenilin/KChip3. We performed the western blot experiment again and found that the antibody is indeed not specific for DREAM/Calsenilin/KChip3. Thus, all of the biochemical data reported in this paper where we used this anti-DREAM antibody must be discounted. The reason why the unspecific effect was not apparent in our published data has been recently investigated, but without any clear answer, probably because the antibody used in the published paper has suffered from some problem from its original use until the present.The results we reported in this paper on learning and memory, electrophysiology, gene expression, and aging phenotypes are not affected by this problem. Since the publication of our paper, another group has shown, in experiments with a different DREAM/Calsenilin/KChip3 mutant line, that DREAM/Calsenilin/KChip3 is involved in learning and memory [1], confirming our basic findings. Of note, this second paper suggested different mechanisms of DREAM function in synaptic plasticity.