The neuronal response to a Ca2+ stimulus is a complex process involving direct Ca2+/calmodulin (CaM) actions as well as secondary activation of multiple signaling pathways such as cAMP and ERK (extracellular signal-regulated kinase). These signals can act in both the cytoplasm and the nucleus to control gene expression. To dissect the role of nuclear from cytoplasmic Ca2+/CaM signaling in memory formation, we generated transgenic mice that express a dominant inhibitor of Ca2+/CaM selectively in the nuclei of forebrain neurons and only after the animals reach adulthood. These mice showed diminished neuronal activity-induced phosphorylation of cAMP response element-binding protein, reduced expression of activity-induced genes, altered maximum levels of hippocampal long-term potentiation, and severely impaired formation of long-term, but not short-term, memory. Our results demonstrate that nuclear Ca2+/CaM signaling plays a critical role in memory consolidation in the mouse.
"CaM is a major Ca 2+ -binding protein found in the central nervous system. Although a large number of studies have investigated the effects of impairing enzymes targeted by CaM (e.g., NOS, CaMKII, MAPK) on learning and memory, there are relatively few reports about the effects of direct inhibition of CaM (Malenka et al. 1989; Nakazawa et al. 1995; Margrie et al. 1998; Limback-Stokin et al. 2004). We investigated the effect of CaM inhibition on olfactory learning and memory in honeybees using three structurally different CaM antagonists, W-7, TFP, and R24571, delivered at different concentrations (Fig. 4). "
[Show abstract][Hide abstract] ABSTRACT: Memory is a dynamic process that allows encoding, storage, and retrieval of information acquired through individual experience. In the honeybee Apis mellifera, olfactory conditioning of the proboscis extension response (PER) has shown that besides short-term memory (STM) and mid-term memory (MTM), two phases of long-term memory (LTM) are formed upon multiple-trial conditioning: an early phase (e-LTM) which depends on translation from already available mRNA, and a late phase (l-LTM) which requires de novo transcription and translation. Here we combined olfactory PER conditioning and neuropharmacological inhibition and studied the involvement of the NO-cGMP pathway, and of specific molecules, such as cyclic nucleotide-gated channels (CNG), calmodulin (CaM), adenylyl cyclase (AC), and Ca(2+)/calmodulin-dependent protein kinase (CaMKII), in the formation of olfactory LTM in bees. We show that in addition to NO-cGMP and cAMP-PKA, CNG channels, CaM, AC, and CaMKII also participate in the formation of a l-LTM (72-h post-conditioning) that is specific for the learned odor. Importantly, the same molecules are dispensable for olfactory learning and for the formation of both MTM (in the minute and hour range) and e-LTM (24-h post-conditioning), thus suggesting that the signaling pathways leading to l-LTM or e-LTM involve different molecular actors.
"modeling to test the influence of the different aspects of the nuclear geometry on the dynamics of calcium transients in the cell nucleus following increases in the cytosolic calcium concentration. Nuclear calcium signaling was chosen because it controls gene expression mediated by the CREB/CBP transcription factor complex (Bading et al., 1993; Hardingham et al., 1997, 2001a; Chawla et al., 1998) that is important for adaptive processes in the brain including neuronal survival , plasticity, and learning (Milner et al., 1998; Bading, 2000; Lonze and Ginty, 2002; Limbäck-Stokin et al., 2004; Papadia et al., 2005). Nuclear calcium transients are triggered by calcium entry into neurons either through synaptic NMDA receptors or L-type voltage-gated calcium channels (Hardingham et al., 2001a, 2002). "
[Show abstract][Hide abstract] ABSTRACT: Synaptic activity initiates many adaptive responses in neurons. Here we report a novel form of structural plasticity in dissociated hippocampal cultures and slice preparations. Using a recently developed algorithm for three-dimensional image reconstruction and quantitative measurements of cell organelles, we found that many nuclei from hippocampal neurons are highly infolded and form unequally sized nuclear compartments. Nuclear infoldings are dynamic structures, which can radically transform the geometry of the nucleus in response to neuronal activity. Action potential bursting causing synaptic NMDA receptor activation dramatically increases the number of infolded nuclei via a process that requires the ERK-MAP kinase pathway and new protein synthesis. In contrast, death-signaling pathways triggered by extrasynaptic NMDA receptors cause a rapid loss of nuclear infoldings. Compared with near-spherical nuclei, infolded nuclei have a larger surface and increased nuclear pore complex immunoreactivity. Nuclear calcium signals evoked by cytosolic calcium transients are larger in small nuclear compartments than in the large compartments of the same nucleus; moreover, small compartments are more efficient in temporally resolving calcium signals induced by trains of action potentials in the theta frequency range (5 Hz). Synaptic activity-induced phosphorylation of histone H3 on serine 10 was more robust in neurons with infolded nuclei compared with neurons with near-spherical nuclei, suggesting a functional link between nuclear geometry and transcriptional regulation. The translation of synaptic activity-induced signaling events into changes in nuclear geometry facilitates the relay of calcium signals to the nucleus, may lead to the formation of nuclear signaling microdomains, and could enhance signal-regulated transcription.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 11/2009; 29(47):14687-700. DOI:10.1523/JNEUROSCI.1160-09.2009 · 6.34 Impact Factor
"The presence of CaM in the nucleus of several cell types, including astrocytes, is well documented and a dynamic regulation of its level in this cell compartment has been suggested (Bachs et al., 1994; Agell et al., 1998; Chin and Means, 2000; Limbäck-Stokin et al., 2004). The distribution of CaM in the nucleus of quiescent and dividing astrocytes , as analysed by immunogold, is similar to that Fig. 7. Immunogold of aII-spectrin in control growing astrocytes. "
[Show abstract][Hide abstract] ABSTRACT: The distribution of calmodulin (CaM) and the CaM-binding proteins neuronal nitric oxide synthase (nNOS) and alphaII-spectrin (alpha-fodrin) in the nucleus of growing and differentiated astrocytes was analysed using immunogold electronmicroscopy. We also analysed the effect of moderate ethanol exposure on these proteins. For this, female Wistar rat were fed with an alcoholic liquid diet and exposed to males after several weeks. Pregnant rats were fed with this diet and, after birth, the foetuses brains were used to establish primary cultures of astrocytes. Astrocytes from control and ethanol-exposed rats foetuses were cultured in the absence or presence of ethanol (30 mM) for 7 days (growing cells) and 21 days (differentiated astrocytes). Our results indicate that all the proteins studied appeared mainly on the condensed chromatin of both control- and alcohol-exposed cells and that there are significant variations in the amount of these proteins between quiescent and dividing astrocytes. Altogether, we have not found a co-localisation between CaM and the CaM-binding proteins.
Toxicology in Vitro 10/2007; 21(6):1039-49. DOI:10.1016/j.tiv.2007.03.008 · 2.90 Impact Factor
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