Nuclear Ca²+ and the cAMP Response Element-Binding Protein Family Mediate a Late Phase of Activity-Dependent Neuroprotection

Abstract

The mechanism by which physiological synaptic NMDA receptor activity promotes neuronal survival is not well understood. Here, we show that that an episode of synaptic activity can promote neuroprotection for a long time after that activity has ceased. This long-lasting or "late phase" of neuroprotection is dependent on nuclear calcium signaling and cAMP response element (CRE)-mediated gene expression. In contrast, neuroprotection evoked acutely by ongoing synaptic activity relies solely on the activation of the phosphatidylinositol 3-kinase/Akt pathway. This "acute phase" does not require nuclear calcium signaling and is independent of activation of the CRE-binding protein (CREB) family of transcription factors. Thus, activity-dependent neuroprotection comprises two mechanistically distinct phases that differ in their spatial requirements for calcium and in their reliance on the CREB family.

NR2D-containing NMDA receptors mediate tissue plasminogen activator-promoted neuronal excitotoxicity

“…25,36 Also relevant to this data, increased synaptic activity induced in cortical cultures protects neurons against neurotoxin in an NMDAR-dependent manner. 26,37 Although in the presence of MK-801, tPA reduced neurotoxicity induced by NMDA after a pre-treatment with Bic þ 4-AP, it had no Figure 8 PPDA does not influence NMDA-mediated neurotoxicity after a pre-synaptic priming. (a) Neurons (12-14 DIV) were subjected or not to a 15 min incubation in the presence of KCl (75 mM), before NMDA (50 mM) exposure alone or in the presence of tPA (20 mg/ml) for 60 min.…”

Synaptic Activity Induces Dramatic Changes in the Geometry of the Cell Nucleus: Interplay between Nuclear Structure, Histone H3 Phosphorylation, and Nuclear Calcium Signaling

“…We therefore used mathematical 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, 1997Hardingham et al, , 2001aChawla 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(Hardingham et al, , 2002.…”

Epigenetic mechanisms in the dentate gyrus act as a molecular switch in hippocampus-associated memory formation

“…20,35 However, in contrast to H3S10p-K14ac and c-Fos induction, CREB phosphorylation occurs in virtually all dentate gyrus neurons after forced swimming. 29 Therefore, although presently a role of pCREB/CBP cannot be excluded, it seems that pCREB may be playing a rather general role (such as neuroprotection 36 ) in the dentate gyrus after a psychological challenge. Recently, we discovered that challenges like forced swimming and novelty result in the phosphorylation of the E twenty-six (ETS)-domain protein Elk-1 (Ets-like protein-1, [37][38][39] ) specifically in pERK1/2/pMSK1/H3S10p-K14ac/c-Fospositive neurons of the dentate gyrus.…”