Roles of CREB in the regulation of FMRP by group I metabotropic glutamate receptors in cingulate cortex
© Wang et al.; licensee BioMed Central Ltd. 2012
Received: 25 June 2012
Accepted: 2 August 2012
Published: 6 August 2012
Fragile X syndrome is caused by lack of fragile X mental retardation protein (FMRP) due to silencing of the FMR1 gene. The metabotropic glutamate receptors (mGluRs) in the central nervous system contribute to higher brain functions including learning/memory, mental disorders and persistent pain. The transcription factor cyclic AMP-responsive element binding protein (CREB) is involved in important neuronal functions, such as synaptic plasticity and neuronal survival. Our recent study has shown that stimulation of Group I mGluRs upregulated FMRP and activated CREB in anterior cingulate cortex (ACC), a key region for brain cognitive and executive functions, suggesting that activation of Group I mGluRs may upregulate FMRP through CREB signaling pathway.
In this study, we demonstrate that CREB contributes to the regulation of FMRP by Group I mGluRs. In ACC neurons of adult mice overexpressing dominant active CREB mutant, the upregulation of FMRP by stimulating Group I mGluR is enhanced compared to wild-type mice. However, the regulation of FMRP by Group I mGluRs is not altered by overexpression of Ca2+-insensitive mutant form of downstream regulatory element antagonist modulator (DREAM), a transcriptional repressor involved in synaptic transmission and plasticity.
Our study has provided further evidence for CREB involvement in regulation of FMRP by Group I mGluRs in ACC neurons, and may help to elucidate the pathogenesis of fragile X syndrome.
KeywordsCREB FMRP Group I mGluRs Gene expression Cingulate cortex Fragile X syndrome
Fragile X mental retardation protein
Metabotropic glutamate receptors
Ca2+/calmodulin-dependent protein kinase IV
Adenylyl cyclase 1
Anterior cingulate cortex
Cyclic AMP-responsive element binding protein
Downstream regulatory element antagonist modulator
cAMP dependent kinase
Fragile X syndrome, the most common cause of inherited mental retardation and autism spectrum disorders, is caused by mutations of the FMR1 gene that encodes the fragile X mental retardation protein (FMRP) [1–9]. FMRP, an mRNA binding protein, is involved in activity-dependent synaptic plasticity through regulation of local protein synthesis at synapses [2, 7, 9–16]. It normally functions as a repressor of translation of specific mRNAs [10, 15, 17–19]. The abnormal functions of Group I mGluR-dependent synaptic plasticity have been observed in hippocampus of Fmr1 knockout (KO) mice [16, 17, 20–23]. It is believed that the protein synthesis downstream of Group I mGluRs are exaggerated due to the lack of FMRP in fragile X syndrome [8, 17, 21, 24].
The anterior cingulate cortex (ACC) is important for cognitive learning, fear memory and persistent pain [25–31]. Previous studies have shown that trace fear memory is impaired in Fmr1 KO mice, accompanied by alterations in synaptic plasticity in ACC, suggesting that the dysfunction of ACC due to lack of FMRP may be responsible for certain types of mental disorders in fragile X syndrome [27, 32]. The mGluRs in ACC contribute to activity-dependent synaptic plasticity and behavioral fear memory [33, 34]. The regulation of FMRP by mGluRs has been mostly studied in hippocampal neurons [11, 17, 21, 35, 36]. Our recent study has found that activation of Group I mGluRs regulates the expression of FMRP in ACC neurons and activates cyclic AMP-responsive element binding protein (CREB) [37, 38], a transcriptional factor which plays many functional roles in central nervous system, such as neuronal survival, synaptic plasticity, learning and memory [39–45]. These findings indicate possible roles of CREB in linking mGluRs to FMRP in ACC. Loss of this signaling pathway may contribute to the pathogenesis of fragile X syndrome.
In the present study, we have demonstrated that CREB is involved in the regulation of FMRP by Group I mGluRs. In cingulate cortex from transgenic mice overexpressing dominant active CREB (Y134F) mutant which displays a higher affinity with cAMP dependent kinase (PKA) compared to wild-type (WT) CREB [46, 47], we found the upregulation of FMRP by stimulating Group I mGluR was enhanced compared to that of WT mice. By contrast, the regulation of FMRP by Group I mGluRs was not affected by overexpression of Ca2+ insentive mutant form of downstream regulatory element antagonist modulator (DREAM), a transcriptional repressor involved in synaptic plasticity, learning and memory [48–50]. We propose that CREB is the key transcription factor in regulation of FMRP by Group I mGluRs in ACC neurons.
Overexpression of dominant active CREB enhances the regulation of FMRP by group I mGluRs in the ACC neurons
Phosphorylated CREB (pCREB) binds to cAMP response element (CRE) site in gene promoters and activates gene transcription [41, 42, 45, 51, 52]. It has been reported that the FMR1 gene promoter contains the CRE site [53, 54]. Our recent study had found that (RS)-3, 5-Dihydroxyphenylglycine ((RS)-3, 5-DHPG) treatment could upregulate FMRP and increase the pCREB levels in ACC slices, suggesting that the regulation of FMRP by Group I mGluRs in ACC neurons likely occurs through CREB activation [37, 38].
Overexpression of Ca2+-insensitive DREAM does not affect the regulation of FMRP by group I mGluRs in the ACC neurons
Since transcriptional repressor DREAM interacts with CREB in a Ca2+ dependent manner and prevents the recruitment of CREB-binding protein (CBP) blocking CRE-dependent gene transcription [48, 56], we next checked whether DREAM might be involved in the regulation of FMRP by Group I mGluRs through CREB signaling pathway. To explore the role of DREAM in the upregulation of FMRP by stimulating Group I mGluRs, we have taken the advantage of transgenic mice overexpressing a Ca2+-insensitive DREAM mutant (TgDREAM) [49, 50]. The TgDREAM mice could develop normally and did not exhibit any abnormalities in brain structures. However, overexpression of mutant DREAM impaired NMDA receptor-mediated synaptic plasticity and contextual fear memory .
We next tested the effect of DHPG (100 μM, 30 min) treatment in ACC slices from TgDREAM mice. Importantly, no difference in the basal levels of FMRP in ACC slices was observed between WT and TgDREAM mice (P > 0.05, compared with WT mice, n = 5, Figure 1C). Furthermore, the increase of FMRP after DHPG treatment was not affected in ACC slices from TgDREAM mice compared to WT mice (199 ± 10% and 201 ± 9% of the WT control levels for WT and TgDREAM mice, respectively. In two-way ANOVA analysis, for genotype, F = 0.10, P = 0.75; for treatment, F = 249.81, P < 0.01; for genotype X treatment, F = 0.001, P = 1.00; n = 5 for each group, Figure 1D). The data indicate that overexpression of Ca2+-insensitive mutant form of DREAM does not affect the upregulation of FMRP induced by Group I mGluR activation, suggesting that DREAM might not be involved in the CREB-dependent regulation of FMRP by Group I mGluRs in ACC neurons.
Putative CREs in the FMR1 promoter
Our previous studies have shown that FMRP is required for the physiological function of ACC [25, 27, 57], the mGluRs in ACC may contribute to the activity-dependent synaptic plasticity and fear memory [33, 34]. Recently, we have provided the direct biochemical evidence that activation of Group I mGluRs upregulates FMRP in ACC neurons of adult mice; the upregulation of FMRP by Group I mGluRs occurs at the transcriptional level, stimulation of Group I mGluRs induced the phosphorylation of CREB in ACC neurons [37, 38]. In this study, we provided further evidence that CREB contributes to the upregulation of FMRP induced by stimulating Group I mGluRs and may act as a key signaling molecule linking Group I mGluRs and FMRP in cingulate cortex.
Studies on signaling pathway of CREB activation by Group I mGluRs in cingulate cortex
Effects on CREB phosphorylation induced by DHPG
CaMKIV over expression
DREAM, a multifunctional Ca2+-binding protein, contributes to synaptic plasticity, and behavioral learning and memory. As a transcriptional repressor, it can affect CRE-dependent gene transcription by preventing the recruitment of CBP by pCREB [48, 49, 56]. In this study, we found the upregulation of FMRP by stimulating Group I mGluRs was not affected in ACC slices from mice overexpressing Ca2+-insensitive mutant form of DREAM. The data indicates that overexpression of this mutant form of DREAM does not affect basal expression or CREB-dependent FMRP induction by Group I mGluRs. Since the overexpression of TgDREAM has been associated with the repression of different target genes [49, 58, 59], these results suggest that DREAM might not be involved in the regulation of the FMRP in ACC neurons.
We have demonstrated that CREB is critical for regulation of FMRP by Group I mGluRs in ACC neurons by using genetic approaches. Our study has provided further evidence that CREB is involved in regulation of FMRP by Group I mGluRs in cingulate cortex, and may help to further elucidate the molecular and cellular mechanisms underlying fragile X syndrome.
Materials and methods
Adult male C57Bl/6 mice were used in most of experiments. The transgenic mice overexpressing dominant active mutant CREB (Y134F) or Ca2+ insentive DREAM were generated and maintained as reported previously [47, 50]. All mice were housed under a 12:12 light cycle with food and water provided ad libitum. All mouse protocols are in accordance with NIH guidelines and approved by the Animal Care and Use Committee of University of Toronto.
Drugs and antibodies
(RS)-3, 5-DHPG was purchased from Tocris Bioscience (Ellisville, MO). phosphatase inhibitor cocktail 1 and 2 were purchased from Sigma-Aldrich (St. Louis, MO). The anti-FMRP antibody, horseradish peroxidase-linked goat anti-mouse IgG and goat anti-rabbit IgG for Western blot were purchased from Chemicon International (Temecula, CA). The anti-phospho-threonine antibody, anti-CREB antibody and anti-phosph CREB antibody were purchased from Cell Signaling Technology (Danvers, MA). The anti-actin antibody was from Sigma-Aldrich (St. Louis, MO).
Brain slice preparations
Mice were anesthetized with 2% halothane and brain slices (300 μm) containing ACC were cut at 4°C using a Vibratome, in oxygenated artificial cerebrospinal fluid [ACSF; containing the following (in mM): 124 NaCl, 4 KCl, 26 NaHCO3, 2.0 CaCl2, 1.0 MgSO4, 1.0 NaH2PO4, 10 D-glucose, pH 7.4]. The slices were slowly brought to final temperature of 30°C in ACSF gassed with 95% O2/5% CO2 and incubated for at least 1 hour before experiments. Slices then were exposed to different compounds of interest for the indicated times and snap frozen over dry ice. For biochemical experiments, the ACC regions were microdissected and sonicated in ice-cold homogenization buffer containing phosphatase and protease inhibitors.
Western blot analysis
Western blot was conducted as previously described [25, 38]. The brain tissues were dissected and homogenized in lysis buffer containing 10 mM Tris–HCl (pH 7.4), 2 mM EDTA, 1% SDS, 1X protease inhibitor cocktail, and 1X phosphatase inhibitor cocktail 1 and 2. Protein concentration was measured by Bradford protein assay (Bio-Rad, Hercules, CA). Electrophoresis of equal amounts of total protein was performed on NuPAGE 4-12% Bis-Tris Gels (Invitrogen, Carlsbad, CA). Separated proteins were transferred to polyvinylidene fluoride membranes (Pall Corporation, East Hills, NY) at 4°C for analysis. Membranes were probed with 1:3000 dilution of anti-FMRP, or 1:1000 dilution of anti-phospho-CREB (Ser133) and anti-CREB antibodies. The membranes were incubated in the appropriate horseradish peroxidase-coupled secondary antibody diluted 1:3000 for 2 h followed by enhanced chemiluminescence (ECL) detection of the proteins with Western Lightning Plus-ECL (PerkinElmer Life and Analytical Science Inc., Waltham, MA) according to the manufacturer’s instructions. To verify equal loading, membranes were also probed with 1:3000 dilution of anti-actin antibody. The density of immunoblots was measured using NIH ImageJ program.
All data were presented as the mean ± S.E.M. Statistical comparisons were performed by paired t-test or two-way ANOVA. In all cases, P < 0.05 is considered statistically significant.
This work was supported by grants from the EJLB-CIHR Michael Smith Chair in Neurosciences and Mental Health, Canada Research Chair, Canadian Institute for Health Research operating grant (MOP-124807), NSERC Discovery Grant (RGPIN 402555) (M. Z.). H. W. was supported by Postdoctoral Fellowship from The Fragile X Research Foundation of Canada. S. K. was supported by Grant-in-Aids for Scientific Research 20380078 and 20658035, and High Technology Research and Priority Areas (Molecular Brain Science) 18022038 and 20022039 from the Ministry of Education, Culture, Sports, Science, and Technology, Japan; Core Research for Evolutional Science and Technology, Japan; and the Research Grant for Nervous and Mental Disorders from the Ministry of Health, Labour, and Welfare, Japan; and grants ERA-Net Neuron (grant nEUROsyn 2008), Ministerio Ciencia e Innovacion (SAF2007-62449) and CIBERNED to J.R.N.
- Belmonte MK, Bourgeron T: Fragile X syndrome and autism at the intersection of genetic and neural networks. Nat Neurosci 2006,9(10):1221–1225.PubMedView Article
- Bhakar AL, Dolen G, Bear MF: The Pathophysiology of Fragile X (and What It Teaches Us about Synapses). Annu Rev Neurosci 2012, 2012:2012.
- Feng Y, Zhang F, Lokey LK, Chastain JL, Lakkis L, Eberhart D, Warren ST: Translational suppression by trinucleotide repeat expansion at FMR1. Science 1995,268(5211):731–734.PubMedView Article
- Garber KB, Visootsak J, Warren ST: Fragile X syndrome. Eur J Hum Genet 2008,16(6):666–672.PubMedView Article
- Huber K: Fragile X syndrome: molecular mechanisms of cognitive dysfunction. Am J Psychiatry 2007,164(4):556.PubMedView Article
- Jin P, Warren ST: New insights into fragile X syndrome: from molecules to neurobehaviors. Trends Biochem Sci 2003,28(3):152–158.PubMedView Article
- Santoro MR, Bray SM, Warren ST: Molecular mechanisms of fragile X syndrome: a twenty-year perspective. Annu Rev Pathol 2011, 7:219–245.PubMedView Article
- Krueger DD, Bear MF: Toward fulfilling the promise of molecular medicine in fragile X syndrome. Annu Rev Med 2011, 62:411–429.PubMedView Article
- Wang T, Bray SM, Warren ST: New perspectives on the biology of fragile X syndrome. Curr Opin Genet Dev 2012,22(3):256–263.PubMedView Article
- Bagni C, Greenough WT: From mRNP trafficking to spine dysmorphogenesis: the roots of fragile X syndrome. Nat Rev Neurosci 2005,6(5):376–387.PubMedView Article
- Bassell GJ, Warren ST: Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function. Neuron 2008,60(2):201–214.PubMedView Article
- Brown V, Small K, Lakkis L, Feng Y, Gunter C, Wilkinson KD, Warren ST: Purified recombinant Fmrp exhibits selective RNA binding as an intrinsic property of the fragile X mental retardation protein. J Biol Chem 1998,273(25):15521–15527.PubMedView Article
- Costa-Mattioli M, Sossin WS, Klann E, Sonenberg N: Translational control of long-lasting synaptic plasticity and memory. Neuron 2009,61(1):10–26.PubMedView Article
- Fahling M, Mrowka R, Steege A, Kirschner KM, Benko E, Forstera B, Persson PB, Thiele BJ, Meier JC, Scholz H: Translational regulation of the human achaete-scute homologue-1 by fragile X mental retardation protein. J Biol Chem 2009,284(7):4255–4266.PubMedView Article
- Greenough WT, Klintsova AY, Irwin SA, Galvez R, Bates KE, Weiler IJ: Synaptic regulation of protein synthesis and the fragile X protein. Proc Natl Acad Sci U S A 2001,98(13):7101–7106.PubMedView Article
- Huber KM, Gallagher SM, Warren ST, Bear MF: Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc Natl Acad Sci U S A 2002,99(11):7746–7750.PubMedView Article
- Bear MF, Huber KM, Warren ST: The mGluR theory of fragile X mental retardation. Trends Neurosci 2004,27(7):370–377.PubMedView Article
- Grossman AW, Aldridge GM, Weiler IJ, Greenough WT: Local protein synthesis and spine morphogenesis: Fragile X syndrome and beyond. J Neurosci 2006,26(27):7151–7155.PubMedView Article
- Kao DI, Aldridge GM, Weiler IJ, Greenough WT: Altered mRNA transport, docking, and protein translation in neurons lacking fragile X mental retardation protein. Proc Natl Acad Sci U S A 2010,107(35):15601–15606.PubMedView Article
- Gross C, Berry-Kravis EM, Bassell GJ: Therapeutic strategies in fragile X syndrome: dysregulated mGluR signaling and beyond. Neuropsychopharmacology 2012,37(1):178–195.PubMedView Article
- Hou L, Antion MD, Hu D, Spencer CM, Paylor R, Klann E: Dynamic translational and proteasomal regulation of fragile X mental retardation protein controls mGluR-dependent long-term depression. Neuron 2006,51(4):441–454.PubMedView Article
- Nakamoto M, Nalavadi V, Epstein MP, Narayanan U, Bassell GJ, Warren ST: Fragile X mental retardation protein deficiency leads to excessive mGluR5-dependent internalization of AMPA receptors. Proc Natl Acad Sci U S A 2007,104(39):15537–15542.PubMedView Article
- Osterweil EK, Krueger DD, Reinhold K, Bear MF: Hypersensitivity to mGluR5 and ERK1/2 leads to excessive protein synthesis in the hippocampus of a mouse model of fragile X syndrome. J Neurosci 2010,30(46):15616–15627.PubMedView Article
- Richter JD, Klann E: Making synaptic plasticity and memory last: mechanisms of translational regulation. Genes Dev 2009,23(1):1–11.PubMedView Article
- Wang H, Wu LJ, Kim SS, Lee FJ, Gong B, Toyoda H, Ren M, Shang YZ, Xu H, Liu F, et al.: FMRP acts as a key messenger for dopamine modulation in the forebrain. Neuron 2008,59(4):634–647.PubMedView Article
- Wang H, Xu H, Wu LJ, Kim SS, Chen T, Koga K, Descalzi G, Gong B, Vadakkan KI, Zhang X, et al.: Identification of an adenylyl cyclase inhibitor for treating neuropathic and inflammatory pain. Sci Transl Med 2011,3(65):65–63.View Article
- Zhao MG, Toyoda H, Ko SW, Ding HK, Wu LJ, Zhuo M: Deficits in trace fear memory and long-term potentiation in a mouse model for fragile X syndrome. J Neurosci 2005,25(32):7385–7392.PubMedView Article
- Zhuo M: Molecular mechanisms of pain in the anterior cingulate cortex. J Neurosci Res 2006,84(5):927–933.PubMedView Article
- Zhuo M: Cortical excitation and chronic pain. Trends Neurosci 2008,31(4):199–207.PubMedView Article
- Han CJ, O’Tuathaigh CM, van Trigt L, Quinn JJ, Fanselow MS, Mongeau R, Koch C, Anderson DJ: Trace but not delay fear conditioning requires attention and the anterior cingulate cortex. Proc Natl Acad Sci U S A 2003,100(22):13087–13092.PubMedView Article
- Frankland PW, Bontempi B, Talton LE, Kaczmarek L, Silva AJ: The involvement of the anterior cingulate cortex in remote contextual fear memory. Science 2004,304(5672):881–883.PubMedView Article
- Hayashi ML, Rao BS, Seo JS, Choi HS, Dolan BM, Choi SY, Chattarji S, Tonegawa S: Inhibition of p21-activated kinase rescues symptoms of fragile X syndrome in mice. Proc Natl Acad Sci U S A 2007,104(27):11489–11494.PubMedView Article
- Tang J, Ko S, Ding HK, Qiu CS, Calejesan AA, Zhuo M: Pavlovian fear memory induced by activation in the anterior cingulate cortex. Mol Pain 2005,1(1):6.PubMedView Article
- Wei F, Li P, Zhuo M: Loss of synaptic depression in mammalian anterior cingulate cortex after amputation. J Neurosci 1999,19(21):9346–9354.PubMed
- Weiler IJ, Spangler CC, Klintsova AY, Grossman AW, Kim SH, Bertaina-Anglade V, Khaliq H, de Vries FE, Lambers FA, Hatia F, et al.: Fragile X mental retardation protein is necessary for neurotransmitter-activated protein translation at synapses. Proc Natl Acad Sci U S A 2004,101(50):17504–17509.PubMedView Article
- Nosyreva ED, Huber KM: Metabotropic receptor-dependent long-term depression persists in the absence of protein synthesis in the mouse model of fragile X syndrome. J Neurophysiol 2006,95(5):3291–3295.PubMedView Article
- Wang H, Fukushima H, Kida S, Zhuo M: Ca2+/calmodulin-dependent protein kinase IV links group I metabotropic glutamate receptors to fragile X mental retardation protein in cingulate cortex. J Biol Chem 2009,284(28):18953–18962.PubMedView Article
- Wang H, Wu LJ, Zhang F, Zhuo M: Roles of calcium-stimulated adenylyl cyclase and calmodulin-dependent protein kinase IV in the regulation of FMRP by group I metabotropic glutamate receptors. J Neurosci 2008,28(17):4385–4397.PubMedView Article
- Ao H, Ko SW, Zhuo M: CREB activity maintains the survival of cingulate cortical pyramidal neurons in the adult mouse brain. Mol Pain 2006, 2:15.PubMedView Article
- Barco A, Patterson SL, Alarcon JM, Gromova P, Mata-Roig M, Morozov A, Kandel ER: Gene expression profiling of facilitated L-LTP in VP16-CREB mice reveals that BDNF is critical for the maintenance of LTP and its synaptic capture. Neuron 2005,48(1):123–137.PubMedView Article
- Hardingham GE, Bading H: Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci 2010,11(10):682–696.PubMedView Article
- Lonze BE, Ginty DD: Function and regulation of CREB family transcription factors in the nervous system. Neuron 2002,35(4):605–623.PubMedView Article
- Wang H, Gong B, Vadakkan KI, Toyoda H, Kaang BK, Zhuo M: Genetic evidence for adenylyl cyclase 1 as a target for preventing neuronal excitotoxicity mediated by N-methyl-D-aspartate receptors. J Biol Chem 2007,282(2):1507–1517.PubMedView Article
- Wheeler DG, Groth RD, Ma H, Barrett CF, Owen SF, Safa P, Tsien RW: Ca(V)1 and Ca(V)2 Channels Engage Distinct Modes of Ca(2+) Signaling to Control CREB-Dependent Gene Expression. Cell 2012,149(5):1112–1124.PubMedView Article
- Wu GY, Deisseroth K, Tsien RW: Activity-dependent CREB phosphorylation: convergence of a fast, sensitive calmodulin kinase pathway and a slow, less sensitive mitogen-activated protein kinase pathway. Proc Natl Acad Sci U S A 2001,98(5):2808–2813.PubMedView Article
- Du K, Asahara H, Jhala US, Wagner BL, Montminy M: Characterization of a CREB gain-of-function mutant with constitutive transcriptional activity in vivo. Mol Cell Biol 2000,20(12):4320–4327.PubMedView Article
- Suzuki A, Fukushima H, Mukawa T, Toyoda H, Wu LJ, Zhao MG, Xu H, Shang Y, Endoh K, Iwamoto T, et al.: Upregulation of CREB-Mediated Transcription Enhances Both Short- and Long-Term Memory. J Neurosci 2011,31(24):8786–8802.PubMedView Article
- Alexander JC, McDermott CM, Tunur T, Rands V, Stelly C, Karhson D, Bowlby MR, An WF, Sweatt JD, Schrader LA: The role of calsenilin/DREAM/KChIP3 in contextual fear conditioning. Learn Mem 2009,16(3):167–177.PubMedView Article
- Gomez-Villafuertes R, Torres B, Barrio J, Savignac M, Gabellini N, Rizzato F, Pintado B, Gutierrez-Adan A, Mellstrom B, Carafoli E, et al.: Downstream regulatory element antagonist modulator regulates Ca2+ homeostasis and viability in cerebellar neurons. J Neurosci 2005,25(47):10822–10830.PubMedView Article
- Wu LJ, Mellstrom B, Wang H, Ren M, Domingo S, Kim SS, Li XY, Chen T, Naranjo JR, Zhuo M: DREAM (downstream regulatory element antagonist modulator) contributes to synaptic depression and contextual fear memory. Mol Brain 2010, 3:3.PubMedView Article
- Shaywitz AJ, Greenberg ME: CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem 1999, 68:821–861.PubMedView Article
- Kandel ER: The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB. Mol Brain 2012,5(1):14.PubMedView Article
- Hwu WL, Wang TR, Lee YM: FMR1 enhancer is regulated by cAMP through a cAMP-responsive element. DNA Cell Biol 1997,16(4):449–453.PubMedView Article
- Smith KT, Nicholls RD, Reines D: The gene encoding the fragile X RNA-binding protein is controlled by nuclear respiratory factor 2 and the CREB family of transcription factors. Nucleic Acids Res 2006,34(4):1205–1215.PubMedView Article
- Benito E, Barco A: CREB’s control of intrinsic and synaptic plasticity: implications for CREB-dependent memory models. Trends Neurosci 2010,33(5):230–240.PubMedView Article
- Ledo F, Kremer L, Mellstrom B, Naranjo JR: Ca2 + −dependent block of CREB-CBP transcription by repressor DREAM. Embo J 2002,21(17):4583–4592.PubMedView Article
- Wang H, Kim SS, Zhuo M: Roles of fragile X mental retardation protein in dopaminergic stimulation-induced synapse-associated protein synthesis and subsequent alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-4-propionate (AMPA) receptor internalization. J Biol Chem 2010,285(28):21888–21901.PubMedView Article
- Rivera-Arconada I, Benedet T, Roza C, Torres B, Barrio J, Krzyzanowska A, Avendano C, Mellstrom B, Lopez-Garcia JA, Naranjo JR: DREAM regulates BDNF-dependent spinal sensitization. Mol Pain 2010, 6:95.PubMedView Article
- Savignac M, Pintado B, Gutierrez-Adan A, Palczewska M, Mellstrom B, Naranjo JR: Transcriptional repressor DREAM regulates T-lymphocyte proliferation and cytokine gene expression. Embo J 2005,24(20):3555–3564.PubMedView Article
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