Lack of DREAM Protein Enhances Learning and Memory and Slows Brain Aging

Abstract

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.

Histone H1 Poly[ADP]-Ribosylation Regulates the Chromatin Alterations Required for Learning Consolidation

“…In Aplysia, PARP-1 activation is required for the transcription of ribosomal RNAs and ribosomal proteins (Hernández et al, 2009). Conversely, NF-Band CREB-dependent gene expression is required for learning and memory stabilization in mammals (Barco et al, 2002;Levenson et al, 2004b;Vecsey et al, 2007;Ahn et al, 2008;Fontán-Lozano et al, 2009) (for review, see Alberini, 2009). Our gene expression analysis in the hippocampus after OR training demonstrated the increase in NF-B and CREB gene targets and, in both cases, training-induced NF-B-and CREB-dependent gene expression required of PARP-1 activation.…”

Na+–Ca2+Exchanger (NCX3) Knock-Out Mice Display an Impairment in Hippocampal Long-Term Potentiation and Spatial Learning and Memory

“…Conversely, knock-out mice of the NCX3 transcriptional repressor DREAM display enhanced learning and memory performance (Fontán-Lozano et al, 2009). Interestingly, CaMKII␣ expression was significantly reduced in the CA1 area of ncx3 Ϫ/Ϫ mice.…”

The DREAM Protein Negatively Regulates the NMDA Receptor through Interaction with the NR1 Subunit

“…Moreover, the cell-permeable peptide TAT-21-40, constructed according to the critical binding site of DREAM for the NR1 subunit, confers protection against NMDAinduced cell injury in cultured hippocampal neurons and focal ischemic damage in mice by either pretreatment or posttreatment. In summary, our work reveals a novel regulator of NMDARs and provides important evidence for the emerging role of DREAM in learning and memory (Alexander et al, 2009;Fontán-Lozano et al, 2009). The therapeutic potential of the TAT-21-40 peptide may also extend to other pathologies with an excitotoxic component, including hypoxic, ischemic, and traumatic brain damage and neuronal death arising from epileptic seizures and neurodegenerative diseases.…”

“…DREAM knock-out mice display a hypoalgesic phenotype, suggesting a critical role for DREAM in pain modulation (Cheng et al, 2002). In addition, emerging evidence supports the role of DREAM in long-term potentiation (Lilliehook et al, 2003), learning, and memory (Alexander et al, 2009;Fontán-Lozano et al, 2009).…”