Phosphorylation of cAMP Response Element-Binding Protein in Hippocampal Neurons as a Protective Response after Exposure to GlutamateIn Vitroand IschemiaIn Vivo

Abstract

Although accumulating evidence indicates that cAMP response element-binding protein (CREB) phosphorylation mediates not only synaptic plasticity but also survival of certain neurons, it remains uncertain whether CREB phosphorylation induced after metabolic insult leads to CRE-mediated gene transcription and is involved in cell survival or not. In the present study, we clarified that (1) CREB phosphorylation and ischemic tolerance induced after preconditioning ischemia in the hippocampal neurons was abolished by MK801 administration in gerbil global ischemia model, (2) CREB phosphorylation induced after exposure to glutamate in cultured neurons was inhibited by removal of extracellular calcium, by MK801 and by an inhibitor of calcium-calmodulin-dependent protein kinase (CaMK) II and IV, (3) inhibitor of CaMK II-IV or CRE-decoy oligonucleotide suppressed upregulation of BCL-2 expression and accelerated neuronal damage after exposure to glutamate, and (4) CREB phosphorylation induced in the hippocampal neurons after ischemia and in cultured neurons after exposure to glutamate was followed by CRE-mediated gene transcription in transgenic mice with a CRE-LacZ reporter. Our results suggest that CREB phosphorylation in neurons after ischemia and exposure to glutamate is induced by NMDA receptor-gated calcium influx and subsequent activation of CaMK II-IV and that CREB phosphorylation after metabolic stress might show a neuroprotective response through CRE-mediated gene induction.

Stress-induced structural remodeling in hippocampus: Prevention by lithium treatment

“…The Effect of Chronic Stress on pCREB Staining. As reported (23), CREB phosphorylation reflects elevated glutamatergic activity in the hippocampus. There was a significant effect of experi- Post hoc analysis using a Newman-Keuls test indicates that stressed animals had a significantly higher density of pCREB staining than controls in the CA3 (P Ͻ 0.01) and DG (P Ͻ 0.01).…”

“…The dendritic shrinkage in CA3 pyramidal cell neurons after CRS can be blocked by treatment with the anticonvulsant drug, phenytoin, and the antidepressant tianeptine, both of which have been shown to block excitotoxicity (20)(21)(22). In addition, excitotoxic increases in glutamate lead to phosphorylation of cAMP-response element binding (CREB) (23). Moreover, the transcription factor CREB is implicated in stress effects and the pathology of MDD (24), and CREB protein mRNA levels are increased by chronic antidepressant treatment (25).…”

Exercise reverses the harmful effects of consumption of a high-fat diet on synaptic and behavioral plasticity associated to the action of brain-derived neurotrophic factor

“…Indeed, it has been reported that inhibiting the phosphorylation of CREB increases the degree of neuronal injury following insult (Mabuchi et al, 2001). Conformably, RD rats that underwent exercise training performed superlatively on the MWM task, probably by a dynamic utilization of phospho-CREB based on the depletion of total-CREB and inverted correlation between the two.…”

Striatal dopamine–NMDA receptor interactions in the modulation of glutamate release in the substantia nigra pars reticulata in vivo: opposite role for D1 and D2 receptors

“…Indeed, brief stimulation of NMDA receptors in vivo, such as during transient ischemia (Mabuchi et al 2001) or tetanic stimulation of corticostriatal pathways (Charpier and Deniau 1997) was able to trigger persistent biochemical and functional effects, such as CREB phosphorylation and LTP, respectively.…”