A key feature of memory processes is to link different input signals by association and to preserve this coupling at the level of synaptic connections. Late-phase long-term potentiation (L-LTP), a form of synaptic plasticity thought to encode long-term memory, requires gene transcription and protein synthesis. In this study, we report that a recently cloned coactivator of cAMP-response elementbinding protein (CREB), called transducer of regulated CREB activity 1 (TORC1), contributes to this process by sensing the coincidence of calcium and cAMP signals in neurons and by converting it into a transcriptional response that leads to the synthesis of factors required for enhanced synaptic transmission. We provide evidence that TORC1 is involved in L-LTP maintenance at the Schaffer collateral-CA1 synapses in the hippocampus.BDNF ͉ calcineurin ͉ cAMP-response element-binding protein ͉ long-term potentiation ͉ memory T ransducers of regulated cAMP-response element-binding protein (CREB) activity (TORCs) are newly discovered coactivators that dramatically increase CREB's transcriptional activity independently of CREB Ser-133 phosphorylation (1, 2). Recently, it has been shown that TORC2 functions as a pancreatic coincidence detector. In insulinoma cells, glucose and gut hormones, via respective activation of L-type calcium channels and the cAMP pathway, synergistically promote the dephosphorylation and the concomitant nuclear translocation of TORC2 (3). In the brain, encoding and storing associative memories requires detection of the coincidence of different input signals and translation of these associations into changes in the number, structure, or function of synapses. Therefore, it appears that short-lived coincidences result in the transcriptional activation of genes encoding factors required for enhanced synaptic transmission. TORCs present two features that neurons could use to create an association: they can detect the coincidence of the two most important second messengers, calcium and cAMP, and they are potent coactivators of CREB, a transcription factor known to drive the expression of genes underlying synaptic plasticity, late-phase long-term potentiation (L-LTP), learning, and memory (4-7).CREB-dependent promoters have been generally thought to respond to various intracellular and extracellular cues by the stimulus-dependent phosphorylation of CREB at Ser-133 and resultant recruitment of the coactivator CREB binding protein (CBP) (5,6,8,9). Modification of CREB at this site often mirrors the activation of neurons, leading to the idea that the expression of plasticity-related genes relies on CREB/CBP interaction. However, some studies revealing a discrepancy between CREB phosphorylation and CREB-mediated gene transcription have challenged this model. For instance, monocular deprivation induces LacZ expression in the visual cortex of cAMP-response element (CRE)-LacZ transgenic mice (10), whereas phosphorylation of CREB at Ser-133 remains static (11). Similarly, the mechanism underlying CREB activation during L...
CCAAT/enhancer-binding protein (C/EBP) family members are transcription factors involved in important physiological processes, such as cellular proliferation and differentiation, regulation of energy homeostasis, inflammation, and hematopoiesis. Transcriptional activation by C/EBP␣ and C/EBP involves the coactivators CREB-binding protein (CBP) and p300, which promote transcription by acetylating histones and recruiting basal transcription factors. In this study, we show that C/EBP␦ is also using CBP as a coactivator. Based on sequence homology with C/EBP␣ and -, we identify in C/EBP␦ two conserved amino acid segments that are necessary for the physical interaction with CBP. Using reporter gene assays, we demonstrate that mutation of these residues prevents CBP recruitment and diminishes the transactivating potential of C/EBP␦. In addition, our results indicate that C/EBP family members not only recruit CBP but specifically induce its phosphorylation. We provide evidence that CBP phosphorylation depends on its interaction with C/EBP␦ and define point mutations within one of the two conserved amino acid segments of C/EBP␦ that abolish CBP phosphorylation as well as transcriptional activation, suggesting that this new mechanism could be important for C/EBP-mediated transcription.The CCAAT/enhancer-binding protein (C/EBP) 1 family is composed of pleiotropic transcription factors involved in tissuespecific metabolic gene transcription, in signal transduction activated by several cytokines, and in cell differentiation (for a review, see Refs. 1-7). Six members of the family have been described so far: C/EBP␣, C/EBP, C/EBP␦, C/EBP␥, C/EBP⑀, and C/EBP (8). C/EBP isoforms bind to their cognate DNA element through a bipartite domain called bZIP. This domain consists of a basic region, contacting DNA, and a homo-or heterodimer-forming region called the leucine zipper (9). Because of the high conservation in the bZIP domain, C/EBP family members are able to form homo-or heterodimers, and all, except C/EBP , bind to the same cis-regulatory elements.C/EBP␣, C/EBP, and C/EBP␦ are involved in terminal differentiation of a variety of cells including adipocytes (10), hepatocytes (11,12), gut epithelial cells (13), macrophages (14), myelomonocytes (15), and neurons (16,17). In the nervous system, the role of C/EBP family members is not characterized as well as, for instance, in adipocytes or hepatocytes. However, a recent study suggests that they are essential for cortical progenitor cells to become postmitotic neurons (16). Interestingly, certain C/EBP isoforms appear to be involved in learning and memory processes (18 -20), glial or neuronal cell functions (21-23), and neurotrophic factor expression (24).Knock-out mice were generated for different C/EBP isoforms (reviewed in Refs. 7,8,and 10). These C/EBP-deficient mice display various phenotypes extending from perinatal lethality (for C/EBP␣) to subtle abnormalities. These different phenotypes suggest that C/EBP family members are not functionally redundant, which, to a cer...
The permanganate/oxalate reaction has been known for more than a century; however, its mechanism is still subject to debate. The latest general publication by a French group established a model that involved 14 steps including 8 equilibria. The model was found to be able to simulate experimentally observed phenomena and to account for the bistability in a continually stirred tank reactor (CSTR). However, some earlier reported observations that we found in the literature seem to be inconsistent with this model. We performed electron paramagnetic resonance (EPR) measurements and stopped-flow studies with spectrophotometrical detection to shed light on these contradictions. We found that one of the key steps of the model describing the decomposition of Mn(VII) is not acceptable at least with the indicated rate constant. The only other step in which permanganate is involved is not capable of accounting for the autocatalytic nature. Our striking observation that the reaction still can be autocatalytic when applying a large stoichiometric excess of manganous ions points out that autocatalysis cannot be purely explained by a positive Mn2+ feedback loop. Thus, we propose that the surface-catalyzed formation of colloidal manganese dioxide from Mn(II) and Mn(VII) provides a second positive feedback loop in the reaction.
During hippocampal sharp wave/ripple (SWR) events, previously occurring, sensory input-driven neuronal firing patterns are replayed. Such replay is thought to be important for plasticity-related processes and consolidation of memory traces. It has previously been shown that the electrical stimulation-induced disruption of SWR events interferes with learning in rodents in different experimental paradigms. On the other hand, the cognitive map theory posits that the plastic changes of the firing of hippocampal place cells constitute the electrophysiological counterpart of the spatial learning, observable at the behavioral level. Therefore, we tested whether intact SWR events occurring during the sleep/rest session after the first exploration of a novel environment are needed for the stabilization of the CA1 code, which process requires plasticity. We found that the newly-formed representation in the CA1 has the same level of stability with optogenetic SWR blockade as with a control manipulation that delivered the same amount of light into the brain. Therefore our results suggest that at least in the case of passive exploratory behavior, SWR-related plasticity is dispensable for the stability of CA1 ensembles.
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