Localization of Phosphorylated cAMP Response Element-Binding Protein in Immature Neurons of Adult Hippocampus

Abstract

Neurogenesis continues to occur in the adult hippocampus, although many of the newborn cells degenerate 1-2 weeks after birth. The number and survival of newborn cells are regulated by a variety of environmental stimuli, but very little is known about the intracellular signal transduction pathways that control adult neurogenesis. In the present study, we examine the expression of the phosphorylated cAMP response element-binding protein (pCREB) in immature neurons in adult hippocampus and the role of the cAMP cascade in the survival of new neurons. The results demonstrate that virtually all immature neurons, identified by triple immunohistochemistry for bromodeoxyuridine (BrdU) and polysialic acid-neural cell adhesion molecule (PSA-NCAM), are also positive for pCREB. In addition, upregulation of cAMP (via pharmacological inhibition of cAMP breakdown or by antidepressant treatment) increases the survival of BrdU-positive cells. A possible role for pCREB in the regulation of PSA-NCAM, a marker of immature neurons involved in neuronal remodeling and neurite outgrowth, is supported by cell culture studies demonstrating that the cAMP-CREB pathway regulates the expression of a rate-limiting enzyme responsible for the synthesis of PSA-NCAM. These findings indicate that the cAMP-CREB pathway regulates the survival, and possibly the differentiation and function, of newborn neurons.

N-methyl-d-aspartate receptor independent changes in expression of polysialic acid-neural cell adhesion molecule despite blockade of homosynaptic long-term potentiation and heterosynaptic long-term depression in the awake freely behaving rat dentate gyrus

“…The expression of PSA is regulated by the polysialyltransferase PST and STX mainly at the transcription level but also in post-translational ways (reviewed in Angata and Fukuda, 2003). Since the transcription of at least one of the polysialyltransferases (STX) has been shown to be activated by the cAMP response element binding protein (CREB) (Nakagawa et al, 2002) and that CREB is activated by calcium entry through both NMDA-receptors and L-type voltage-dependent calcium channels (VDCC) (Sheng et al, 1991;Deisseroth et al, 1996;Hardingham et al, 2001), it is probable that HFS induced the activation of CREB through L-type VDCC alone (in the presence of CPP) and thereby increased the STX transcription level. Entry of calcium in this way is also likely to activate post-translational regulatory pathways such as, for instance, the activation of the protein kinase C (PKC), which has been shown to regulate the polysialyltransferases activity in chick ciliary ganglion (Bruses et al, 1995;Bruses and Rutishauser, 1998).…”

Exercise improves memory acquisition and retrieval in the Y-maze task: Relationship with hippocampal neurogenesis.

“…H ϭ hilus; GCL ϭ granule cell layer. Scale bar: 100 m for G and I; 50 m for A, B, E, F, H, and J; 25 m for C and D. occur in newly formed, PSA-NCAM (neural cell adhesion molecule) positive granule neurons during maturation (Nakagawa et al, 2002;Zhu, Lau, Liu, Wei, & Lu, 2004). Because there is an almost complete overlap between DCX expression and NCAM polysialylation (Nacher, Crespo, & McEwen, 2001), we supposed that the pCREB-positive cells in the granule cell layer, located at the border with the hilus, were in fact newly formed neurons.…”

Rapid Effects of Retinoic Acid on CREB and ERK Phosphorylation in Neuronal Cells

“…The neuron-like differentiation of PC12 cells induced by NGF involves activation of the Ras/extracellular signal-regulated kinase (ERK1/2) signaling pathway. Sustained activation of ERK1/2 permits its translocation to the nucleus, where it may modulate gene expression via the phosphorylation of transcription factors or activation of other kinases (Qiu and Green, 1991;Marshall, 1995).The nuclear transcription factor cAMP response elementbinding protein (CREB) is a major downstream target of ERK1/2 signaling that contributes to neuronal differentiation in PC12 cells (Heasley et al, 1991;Ginty et al, 1994) and to brain neuroplasticity (Impey et al, 1998bSgambato et al, 1998;Pham et al, 1999) and neuronal survival (Bonni et al, 1999;Riccio et al, 1999;Nakagawa et al, 2002). CREB binds constitutively to the specific DNA motif, 5Ј-TGACGTCA-3Ј known as CRE, and its activity is triggered by phosphorylation in Ser133 (González and Montminy, 1989).…”