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At least 811 records · Page 45Linked to original sources
PubMed2001

Chronic morphine exposure increases the phosphorylation of MAP kinases and the transcription factor CREB in dorsal root ganglion neurons: an in vitro and in vivo study.

Tolerance to opiates reduces their effectiveness in the treatment of severe pain. Although the mechanisms are unclear, overactivity of pro-nociceptive systems has been proposed to contribute to this phenomenon. We have reported that the development of morphine tolerance significantly increased calcitonin-gene-related-peptide-like immunoreactivity (CGRP-IR) in primary sensory afferents of the spinal dorsal horn, suggesting that changes in pain-related neuropeptides in the dorsal root ganglion (DRG) neurons may be involved (Menard et al., 1996, J. Neurosci., 16, 2342-2351). Recently, we have shown that repeated morphine treatments induced increases in CGRP- and substance P (SP)-IR in cultured DRG, mimicking the in vivo effects (Ma et al., 2000, Neuroscience, 99, 529-539). In this study, we investigated the intracellular signal transduction pathways possibly involved in morphine-induced increases in CGRP- and SP-IR in DRG neurons. Repeated morphine exposure (10-20 microm) for 6 days increased the number of neurons expressing phosphorylated (p) mitogen-activated protein (MAP) kinases, including the extracellular signal-regulated kinase (pERK), c-jun N-terminal kinase (pJNK) and P38 (pP38 MAPK). The number of neurons expressing phosphorylated cAMP responsive element binding protein (pCREB) was also markedly increased in morphine-exposed cultured DRG neurons. pERK-, pP38-, pJNK- and pCREB-IR were colocalized with CGRP-IR in cultured DRG neurons. Naloxone effectively blocked these actions of morphine, whereas a selective MEK1 inhibitor, PD98059, inhibited the morphine-induced increase in the phosphorylation of ERK and CREB, and the expression of CGRP and SP. Moreover, in morphine-tolerant rats, the number of pCREB-, CGRP- and SP-IR neurons in the lumbar DRG was also significantly increased. These in vitro and in vivo data suggest that the phosphorylation of MAP kinases and CREB plays a role in the morphine-induced increase in spinal CGRP and SP levels in primary sensory afferents, contributing to the development of tolerance to opioid-induced analgesia.

Animals↗
PubMed2003

Cyclic AMP response element-binding (CREB)-like proteins in a molluscan brain: cellular localization and learning-induced phosphorylation.

The phosphorylation and the binding to DNA of the nuclear transcription factor, cyclic adenosine 3',5'-monophosphate (cAMP) response element-binding protein (CREB) are conserved key steps in the molecular cascade leading to the formation of long-term memory (LTM). Here, we characterize, for the first time, a CREB1-like protein in the central nervous system (CNS) of Lymnaea, a model system used widely for the study of the fundamental mechanisms of learning and memory. We demonstrate cAMP response element (CRE)-binding activity in CNS protein extracts and show that one of the CRE-binding proteins is recognized by a polyclonal antibody raised to mammalian (human) CREB1. The same antibody detects specific CREB1 immunoreactivity in CNS extracts and in the nuclei of most neurons in the brain. Moreover, phospho-CREB1-specific immunoreactivity is increased significantly in protein extracts of the CNS by forskolin, an activator of adenylate cyclase. The forskolin-induced increase in phospho-CREB1 immunoreactivity is localized to the nuclei of CNS neurons, some of which have an important role in the formation of LTM. Significantly, classical food-reward conditioning increases phospho-CREB1 immunoreactivity in Lymnaea CNS protein extracts. This increase in immunoreactivity is specific to the ganglia that contain the feeding circuitry, which undergoes cellular changes after classical conditioning. This work establishes the expression of a highly conserved functional CREB1-like protein in the CNS of Lymnaea and opens the way for a detailed analysis of the role of CREB proteins in LTM formation in this model system.

Animals↗
PubMed2003

Dopamine D1 receptors mediate CREB phosphorylation via phosphorylation of the NMDA receptor at Ser897-NR1.

Addictive drugs such as amphetamine and cocaine stimulate the dopaminergic system, activate dopamine receptors and induce gene expression throughout the striatum. The signal transduction pathway leading from dopamine receptor stimulation at the synapse to gene expression in the nucleus has not been fully elucidated. Here, we present evidence that D1 receptor stimulation leads to phosphorylation of the transcription factor Ca2+ and cyclic AMP response element binding protein (CREB) in the nucleus by means of NMDA receptor-mediated Ca2+ signaling. Stimulation of D1 receptors induces the phosphorylation of Ser897 on the NR1 subunit by protein kinase A (PKA). This phosphorylation event is crucial for D1 receptor-mediated CREB phosphorylation. Dopamine cannot induce CRE-mediated gene expression in neurons transfected with a phosphorylation-deficient NR1 construct. Moreover, stimulation of D1 receptors or increase in cyclic AMP levels leads to an increase in cytosolic Ca2+ in the presence of glutamate, but not in the absence of glutamate, indicating the ability of dopamine and cyclic AMP to facilitate NMDA channel activity. The recruitment of the NMDA receptor signal transduction pathway by D1 receptors may provide a general mechanism for gene regulation that is fundamental for mechanisms of drug addiction and long-term memory.

Animals↗
PubMed2002

Bimodal regulation of mPeriod promoters by CREB-dependent signaling and CLOCK/BMAL1 activity.

Circadian rhythmicity in mammals is under the control of a molecular pacemaker constituted of clock gene products organized in transcriptional autoregulatory loops. Phase resetting of the clock in response to light involves dynamic changes in the expression of several clock genes. The molecular pathways used by light to influence pacemaker-driven oscillation of clock genes remain poorly understood. We explored the functional integration of both light- and clock-responsive transcriptional regulation at the promoter level of the Period (Per) genes. Three Per genes exist in the mouse. Whereas mPer1 and mPer2 are light-inducible in clock neurons of the hypothalamic suprachiasmatic nucleus, mPer3 is not. We have studied the promoter structure of the three mPer genes and compared their regulation. All three mPer promoters contain E-boxes and respond to the CLOCK/brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like protein 1 (BMAL1) heterodimer. On the other hand, only mPer1 and mPer2 promoters contain bona fide cAMP-responsive elements (CREs) that bind CRE-binding protein (CREB) from suprachiasmatic nucleus protein extracts. The mPer1 promoter is responsive to synergistic activation of the cAMP and mitogen-activated protein kinase pathways, a physiological response that requires integrity of the CRE. In contrast, activation of mPer promoters by CLOCK/BMAL1 occurs regardless of an intact CRE. Altogether, these results constitute strong evidence that CREB acts as a pivotal endpoint of signaling pathways for the regulation of mPer genes. Our results reveal that signaling-dependent activation of mPer genes is distinct from the CLOCK/BMAL1-driven transcription required within the clock feedback loop.

ARNTL Transcription Factors↗
PubMed2001

Prostaglandins are required for CREB activation and cellular proliferation during liver regeneration.

The liver responds to multiple types of injury with an extraordinarily well orchestrated and tightly regulated form of regeneration. The response to partial hepatectomy has been used as a model system to elucidate the molecular basis of this regenerative response. In this study, we used cyclooxygenase (COX)-selective antagonists and -null mice to determine the role of prostaglandin signaling in the response of liver to partial hepatectomy. The results show that liver regeneration is markedly impaired when both COX-1 and COX-2 are inhibited by indocin or by a combination of the COX-1 selective antagonist, SC-560, and the COX-2 selective antagonist, SC-236. Inhibition of COX-2 alone partially inhibits regeneration whereas inhibition of COX-1 alone tends to delay regeneration. Neither the rise in IL-6 nor the activation of signal transducer and activator of transcription-3 (STAT3) that is seen during liver regeneration is inhibited by indocin or the selective COX antagonists. In contrast, indocin treatment prevents the activation of CREB by phosphorylation that occurs during hepatic regeneration. These data indicate that prostaglandin signaling is required during liver regeneration, that COX-2 plays a particularly important role but COX-1 is also involved, and implicate the activation of CREB rather than STAT3 as the mediator of prostaglandin signaling during liver regeneration.

6-Ketoprostaglandin F1 alpha↗
PubMed1998

Rsk-2 activity is necessary for epidermal growth factor-induced phosphorylation of CREB protein and transcription of c-fos gene.

Activation by growth factors of the Ras-dependent signaling cascade results in the induction of p90 ribosomal S6 kinases (p90(rsk)). These are translocated into the nucleus upon phosphorylation by mitogen-activated protein kinases, with which p90(rsk) are physically associated in the cytoplasm. In humans there are three isoforms of the p90(rsk) family, Rsk-1, Rsk-2, and Rsk-3, which are products of distinct genes. Although these isoforms are structurally very similar, little is known about their functional specificity. Recently, mutations in the Rsk-2 gene have been associated with the Coffin-Lowry syndrome (CLS). We have studied a fibroblast cell line established from a CLS patient that bears a nonfunctional Rsk-2. Here we document that in CLS fibroblasts there is a drastic attenuation in the induced Ser-133 phosphorylation of transcription factor CREB (cAMP response element-binding protein) in response to epidermal growth factor stimulation. The effect is specific, since response to serum, cAMP, and UV light is unaltered. Furthermore, epidermal growth factor-induced expression of c-fos is severely impaired in CLS fibroblasts despite normal phosphorylation of serum response factor and Elk-1. Finally, coexpression of Rsk-2 in transfected cells results in the activation of the c-fos promoter via the cAMP-responsive element. Thus, we establish a link in the transduction of a specific growth factor signal to changes in gene expression via the phosphorylation of CREB by Rsk-2.

Cell Line↗
PubMed1998

RSK-B, a novel ribosomal S6 kinase family member, is a CREB kinase under dominant control of p38alpha mitogen-activated protein kinase (p38alphaMAPK).

A novel ribosomal S6 kinase (RSK) family member, RSK-B, was identified in a p38alphaMAPK-baited intracellular interaction screen. RSK-B presents two catalytic domains typical for the RSK family. The protein kinase C-like N-terminal and the calcium/calmodulin kinase-like C-terminal domains both contain conserved ATP-binding and activation consensus sequences. RSK-B is a p38alphaMAPK substrate, and activated by p38alphaMAPK and, more weakly, by ERK1. RSK-B phosphorylates the cAMP response element-binding protein (CREB) and c-Fos peptides. In intracellular assays, RSK-B drives cAMP response element- and AP1-dependent reporter expression. RSK-B locates to the cell nucleus and co-translocates p38alphaMAPK. In conclusion, RSK-B is a novel CREB kinase under dominant p38alphaMAPK control, also phosphorylating additional substrates.

Amino Acid Sequence↗
PubMed1998

Globoside-dependent adhesion of human embryonal carcinoma cells, based on carbohydrate-carbohydrate interaction, initiates signal transduction and induces enhanced activity of transcription factors AP1 and CREB.

Undifferentiated human embryonal carcinoma cells are characterized by high expression of lactoneotetraosylceramide (nLc4), globoside (Gb4), and extended globo-series glycosphingolipids (GSLs) termed "stage-specific embryonic antigens 3 and 4" (SSEA-3 and -4). Expression of these GSLs declines in association with a decline of homotypic adhesion during the differentiation process. Therefore, these GSLs may play an essential role in adhesion among these cells. As an example, human embryonal carcinoma 2102 cells display strong adhesion to plates coated with Gb4 ("Gb4-dependent cell adhesion"). This adhesion, which simulates homotypic 2102 cell aggregation, is based on interaction between Gb4 and nLc4, or between Gb4 and GalGb4 (IV3GalGb4; the major SSEA-3 epitope), as indicated by the following observations: (i) adhesion of 2102 cells or GSL-liposomes to GSL-coated plates in various combinations; (ii) inhibition of Gb4-dependent 2102 cell adhesion by preincubation of cells with anti-SSEA-3 or anti-nLc4 antibodies, or by pretreatment of Gb4-coated plates with aqueous micellar solution of nLc4 or GalGb4; (iii) decline of the cell adhesion in association with retinoic acid-induced differentiation, whereby SSEA-3 and nLc4 levels are reduced. Since cell adhesion is an essential prerequisite for induction of differentiation, as observed at each step of embryogenesis, expression of seven transcription factors following adhesion of 2102 cells to Gb4-coated plates, and to detergent-insoluble substrate adhesion matrix prepared from 2102 cells, were studied. In both types of adhesion, a strong enhancement of AP1 and CREB site binding activity was observed during the early stage (15-60 min following initial adhesion). Although 2102 cells showed strong adhesion to Gg3-coated plates, based on interaction between Gg3 and Gb4, adhesion of the cells to Gg3 did not cause changes of AP1 and CREB activity. No other transcription factors showed changes induced by Gg3- or Gb4-dependent adhesion.

Antigens, Tumor-Associated, Carbohydrate↗
PubMed2000

Sequential serum-dependent activation of CREB and NRF-1 leads to enhanced mitochondrial respiration through the induction of cytochrome c.

Progression through the cell cycle requires ATP for protein synthesis, cytoskeletal rearrangement, chromatin remodeling, and protein degradation. The mechanisms by which mammalian cells increase respiratory capacity and ATP production in preparation for cell division are largely unexplored. Here, we demonstrate that serum induction of cytochrome c mRNA and processed protein in quiescent BALB/3T3 fibroblasts is associated with a marked increase in mitochondrial respiration. Cytochrome c was induced in the absence of any increase in citrate synthase activity or in subunit IV of the cytochrome c oxidase complex mRNA or protein, indicating that the enhanced respiratory rate did not require a general increase in mitochondrial biogenesis or respiratory chain expression. Transfections with a series of cytochrome c promoter mutants showed that both nuclear respiratory factor 1 (NRF-1) and cAMP-response element-binding protein (CREB) binding sites contributed equally to induced expression by serum. Moreover, CREB and NRF-1 were phosphorylated sequentially in response to serum, and the NRF-1 phosphorylation was accompanied by an increase in its ability to trans-activate target gene expression. The results demonstrate that the differential transcriptional expression of cytochrome c, through sequential transcription factor phosphorylations, leads to enhanced mitochondrial respiratory capacity upon serum-induced entry to the cell cycle.

3T3 Cells↗
PubMed2001

Human CREB-binding protein/p300-interacting transactivator with ED-rich tail (CITED) 4, a new member of the CITED family, functions as a co-activator for transcription factor AP-2.

Members of the CREB-binding protein/p300-interacting transactivator with ED-rich tail (CITED) family bind CREB-binding protein and p300 with high affinity and regulate gene transcription. Gene knockout studies indicate that CITED2 is required for neural crest and neural tube development and that it functions as a co-activator for transcription factor AP-2 (TFAP2). Here we describe human CITED4, a new member of this family, which is encoded by a single exon mapping to chromosome 1p34--1p35. CITED4 and p300/CREB-binding protein are present in endogenous naturally occurring complexes, indicating that they interact physiologically. The interaction occurs between the cysteine-histidine-rich domain 1 of p300 and the carboxyl terminus of CITED4. In keeping with this, CITED4 functions as a transactivator when artificially targeted to a promoter element. CITED4 physically interacts with all TFAP2 isoforms in vitro and strongly co-activates all TFAP2 isoforms in Hep3B cells. Co-activation of TFAP2 requires amino-terminal and carboxyl-terminal residues of CITED4. In HepG2 cells, CITED4 is significantly weaker than CITED2 for TFAP2C co-activation. These results suggest that CITED4 may function as a co-activator for TFAP2. They also suggest the existence of cell type- and TFAP2 isoform-specific co-activation by CITED2 and CITED4, which may result in differential modulation of TFAP2 function.

Amino Acid Sequence↗
PubMed2006

Intracellular HIV-Tat expression induces IL-10 synthesis by the CREB-1 transcription factor through Ser133 phosphorylation and its regulation by the ERK1/2 MAPK in human monocytic cells.

Human immunodeficiency virus (HIV)-Tat plays an important role in virus replication and in various aspects of host immune responses, including dysregulation of cytokine production. IL-10, an anti-inflammatory cytokine, is up-regulated during the course of HIV infection representing an important pathway by which HIV may induce immunodeficiency. Here we show that extracellular as well as intracellular Tat induced IL-10 expression in normal human monocytes and promonocytic THP-1 cells. The signaling pathways involved in the regulation of IL-10 production by endogenous Tat remain unknown. To understand the molecular mechanism underlying intracellular Tat-induced IL-10 transcription, we employed a retroviral expression system to investigate the role of MAPKs and the transcription factor(s) involved. Our results suggest that an inhibitor specific for the ERK1/2, PD98059, selectively blocked intracellular Tat-induced IL-10 expression in THP-1 cells. Furthermore, intracellular Tat activated the CREB-1 transcription factor through Ser(133) phosphorylation that was regulated by ERK MAPK as determined by IL-10 promoter analysis and gel shift assays. Overall, our results suggest that intracellular HIV-Tat induces IL-10 transcription by ERK MAPK-dependent CREB-1 transcription factor activation through Ser(133) phosphorylation.

Cyclic AMP Response Element-Binding Protein↗
PubMed2002

The role of CREB and other transcription factors in the pharmacotherapy and etiology of depression.

Psychiatric diseases are genetically complex and consequently, altered programs of gene expression have been hypothesized as the molecular basis of psychopathology. Since transcription factors represent the final communicative link between receptor activation and the orchestration of programs of gene expression, they are prime targets for studies on both the pharmacotherapy and the etiology of depression. The cyclic AMP response element binding protein (CREB) and the glucocorticoid receptor (GR) are altered by chronic treatment with antidepressants. Since it is phosphorylated CREB (pCREB) that determines its transcriptional activity, it is pertinent that some antidepressants have been shown to reduce pCREB in brain in vivo and in tissue culture in vitro. Moreover, pCREB is down-regulated in human fibroblasts from patients with major depression and in postmortem brain of suicide victims with a history of depression. With regard to GR, its mRNA, immunoreactivity, density and cytoplasmic-nuclear translocation are increased by antidepressants. While transcription factor mediated programs of gene expression relevant to either the pharmacotherapy or the etiology of depression are still largely elusive, studies utilizing modern technologies such as differential display and cDNA microarrays promise to lead eventually to the identification of structure and function of psychopathologically relevant target genes.

Animals↗
PubMed2004

Enhancement of cell survival by stromal cell-derived factor-1/CXCL12 involves activation of CREB and induction of Mcl-1 and c-Fos in factor-dependent human cell line MO7e.

Stromal cell-derived factor-1 (SDF-1/CXCL12) enhances the survival of hematopoietic stem and progenitor cells in synergy with other cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), steel factor, and thrombopoietin (TPO), and both the PI3K/Akt and MAPK pathways have been linked to this survival. To further evaluate intracellular signaling involved in SDF-1/CXCL12 survival effects, we investigated modulation of downstream signaling molecules. The synergistic survival enhancement of SDF-1/CXCL12 plus other cytokines were directly linked to enhanced phosphorylation of p70/85S6K and cAMP responsive element binding protein (CREB), as well as enhanced induction of the Bcl-2 family member Mcl-1. Most prominently, c-Fos, a component of AP1 transcription factor, was synergistically induced by SDF-1/CXCL12 plus other cytokines. These results suggest that SDF-1/CXCL12 enhanced cell survival in synergy with other cytokines involves activation of CREB and induction of Mcl-1 and c-Fos.

Blotting, Western↗
PubMed2000

Aeromonas hydrophila AmpH and CepH beta-lactamases: derepressed expression in mutants of Escherichia coli lacking creB.

The class 1 cephalosporinase (CepH) and class 2d oxacillinase (AmpH) from an Aeromonas hydrophila clinical isolate, strain T429125, have been cloned and sequenced. Both enzymes are typical of their equivalents in other species of Aeromonas Both cloned beta-lactamase genes were expressed at a low level in a standard laboratory Escherichia coli strain, but when cloned into a cre deletion E. coli mutant, they were expressed at significantly higher levels. Specific disruption of the creB gene resulted in similar increased levels of beta-lactamase expression, so it was concluded that CreB represses the transcription of ampH and cepH in a cre(+) E. coli strain. The expression of cepH was four times that of ampH in the deltacre mutant because of an additional factor encoded on the cloned T429125 chromosomal fragment containing cepH. This factor was able to trans-activate expression of co-resident ampH in the deltacre mutant such that expression of the two genes was approximately equal. The entire cepH-containing fragment was sequenced, but it contained no genes that were obviously related to any known class of DNA-binding protein.

Aeromonas hydrophila↗
PubMed2000

Expression of the cyclic AMP-dependent transcription factors, CREB, CREM and ATF2, in the human myometrium during pregnancy and labour.

Elevated concentrations of cyclic AMP (cAMP) in the human myometrium may promote uterine quiescence during pregnancy by protein kinase A (PKA)-mediated phosphorylation and subsequent inactivation of myosin light-chain kinase, as well as by the phosphorylation and activation of cAMP-dependent transcription factors. In this context, we show that the altered expression of cAMP response-element binding protein (CREB), cAMP response-element modulator protein (CREM) and activating transcription factor 2 (ATF2) are implicated in the maintenance of myometrial quiescence during fetal maturation and the switch to uterine activation at term. Using electrophoretic mobility shift and super shift assays, as well as immunoblotting of paired myometrial tissue samples from non-pregnant, pregnant non-labouring and spontaneous labouring women, we defined the patterns of expression of various isoforms of these proteins in the human uterus. Here, we report spatio-temporal changes in the expression of a 43 kDa form of CREB, a 28 kDa CREM-like protein, and a novel 28 kDa ATF2-like protein which are differentially expressed, depending on the gestational state of the uterus. Changes in the pattern of expression of these potent transcription factors may have an important role in the control of uterine activity throughout pregnancy.

Activating Transcription Factor 2↗
PubMed2006

The gene encoding the fragile X RNA-binding protein is controlled by nuclear respiratory factor 2 and the CREB family of transcription factors.

FMR1 encodes an RNA-binding protein whose absence results in fragile X mental retardation. In most patients, the FMR1 gene is cytosine-methylated and transcriptionally inactive. NRF-1 and Sp1 are known to bind and stimulate the active, but not the methylated/silenced, FMR1 promoter. Prior analysis has implicated a CRE site in regulation of FMR1 in neural cells but the role of this site is controversial. We now show that a phospho-CREB/ATF family member is bound to this site in vivo. We also find that the histone acetyltransferases CBP and p300 are associated with active FMR1 but are lost at the hypoacetylated fragile X allele. Surprisingly, FMR1 is not cAMP-inducible and resides in a newly recognized subclass of CREB-regulated genes. We have also elucidated a role for NRF-2 as a regulator of FMR1 in vivo through a previously unrecognized and highly conserved recognition site in FMR1. NRF-1 and NRF-2 act additively while NRF-2 synergizes with CREB/ATF at FMR1's promoter. These data add FMR1 to the collection of genes controlled by both NRF-1 and NRF-2 and disfavor its membership in the immediate early response group of genes.

Activating Transcription Factors↗
PubMed2005

Methoxychlor inhibits brain mitochondrial respiration and increases hydrogen peroxide production and CREB phosphorylation.

The organochlorine insecticide methoxychlor (mxc) is an established reproductive toxicant that affects other systems including the central nervous system (CNS), possibly by mechanisms involving oxidative stress. This study tested the hypothesis that mxc inhibits brain mitochondrial respiration, resulting in increased production of reactive oxygen species (ROS). Oxygen electrode measurements of mitochondrial respiration and Amplex Red measurements of H(2)O(2) production were performed with rat brain mitochondria exposed in vitro to mxc (0-10 microg/ml) and with brain mitochondria from mice chronically exposed in vivo to mxc (0-64 mg/kg/day) for 20 days by intraperitoneal injection. In vitro mxc exposure inhibited ADP-dependent respiration (state 3) using both complex I- and II-supported substrates. Similarly, state 3 respiration was inhibited following in vivo mxc exposure using complex I substrates. H(2)O(2) production was stimulated after in vitro mxc treatment in the presence of complex I substrates, but not in mitochondria isolated from in vivo mxc-treated mice. Because previous studies demonstrated a relationship between oxidative stress and CREB phosphorylation, we also tested the hypothesis that mxc elevates phosphorylated CREB (pCREB) in mitochondria. Enzyme-linked immunosorbent assay (ELISA) measurements demonstrated that pCREB immunoreactivity was elevated by in vitro mxc exposure in the presence or absence of respiratory substrates, indicating that stimulation of H(2)O(2) production is not necessary for this effect. These multiple effects of mxc on mitochondria may play an important role in its toxicity, particularly in the CNS.

Animals↗
PubMed2004

Prenatal choline supplementation advances hippocampal development and enhances MAPK and CREB activation.

Choline is an essential nutrient for animals and humans. Previous studies showed that supplementing the maternal diet with choline during the second half of gestation in rats permanently enhances memory performance of the adult offspring. Here we show that prenatal choline supplementation causes a 3-day advancement in the ability of juvenile rats to use relational cues in a water maze task, indicating that the treatment accelerates hippocampal maturation. Moreover, phosphorylation and therefore activation of hippocampal mitogen-activated protein kinase (MAPK) and cAMP-response element binding protein (CREB) in response to stimulation by glutamate, N-methyl-D-aspartate, or depolarizing concentrations of K+ were increased by prenatal choline supplementation and reduced by prenatal choline deficiency. These data provide the first evidence that developmental plasticity of the hippocampal MAPK and CREB signaling pathways is controlled by the supply of a single essential nutrient, choline, during fetal development and point to these pathways as candidate mechanisms for the developmental and long-term cognitive enhancement induced by prenatal choline supplementation.

Animals↗