Nonaka, Mio

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A Janus-Like Role of CREB Protein: Enhancement of Synaptic Property in Mature Neurons and Suppression of Synaptogenesis and Reduced Network Synchrony in Early Development

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     Edinburgh Research Explorer                                      A Janus-like role of CREB proteinCitation for published version:Nonaka, M 2009, 'A Janus-like role of CREB protein: enhancement of synaptic property in mature neuronsand suppression of synaptogenesis and reduced network synchrony in early development' Journal ofNeuroscience, vol 29, no. 20, pp. 6389-91. DOI: 10.1523/JNEUROSCI.1309-09.2009Digital Object Identifier (DOI):10.1523/JNEUROSCI.1309-09.2009Link:Link to publication record in Edinburgh Research ExplorerDocument Version:Publisher's PDF, also known as Version of recordPublished In:Journal of NeurosciencePublisher Rights Statement:Copyright © 2009 Society for NeuroscienceGeneral rightsCopyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s)and / or other copyright owners and it is a condition of accessing these publications that users recognise andabide by the legal requirements associated with these rights.Take down policyThe University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorercontent complies with UK legislation. If you believe that the public display of this file breaches copyright pleasecontact openaccess@ed.ac.uk providing details, and we will remove access to the work immediately andinvestigate your claim.Download date: 28. Apr. 2017Journal ClubEditor’sNote: These short, critical reviewsof recent papers in the Journal, written exclusively by graduate students orpostdoctoralfellows, are intended to summarize the important findings of the paper andprovide additional insight and commentary. Formoreinformation on the format and purpose of the Journal Club, please see http://www.jneurosci.org/misc/ifa_features.shtml.A Janus-Like Role of CREB Protein: Enhancement ofSynaptic Property in Mature Neurons and Suppression ofSynaptogenesis and Reduced Network Synchrony in EarlyDevelopmentMio NonakaDepartment of Neurochemistry, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, JapanReview of Aguado et al. (http://www.jneurosci.org/cgi/content/full/29/2/328)The cAMP response element (CRE)-binding protein (CREB) is a transcriptionfactor that binds to CRE sequences (con-sensus, TGACGTCA) that are presentwithin the promoters of many neuronalgenes and is activated in response to vari-ous signaling cascades. CREB, cAMP-responsive element modulator (CREM),and activating transcription factor-1(ATF-1) constitute the CREB/ATF familyof bZIP transcription factors and regulatemany physiologically critical functionssuch as cell proliferation, survival, differ-entiation, cell morphology, and synapticplasticity (Shaywitz and Greenberg,1999).CREB has several splice variants,among which -, -, and -isoformsfunction in the brain. The first Crebknock-out (Creb1) (Bourtchuladze etal., 1994; Hummler et al., 1994) showedno gross abnormalities of development,likely because CREM and CREB wereupregulated to compensate for the loss ofCREB function (see Table 1 for a sum-mary of Creb and/or Crem knock-outs).To create a full Creb knock-out, Rudolphet al. (1998) disrupted exons that code theessential bZIP domain of CREB. Thismouse, Creb1/ had gross growth de-fects and died perinatally. At embryonicday 18.5 (E18.5), Creb1/ mice hadsmaller corpus callosum and anteriorcommissures, indicating an axonal phe-notype. However, again, CREM was up-regulated in these knock-outs, thus com-plicating the interpretation (Rudolph etal., 1998).For these reasons, it was necessary tocreate a Creb/Crem double knock-outmouse. Furthermore, because CREB playsessential roles in many organs, and to dis-tinguish the contribution of CREB inadult plasticity from CREB’s functionduring development, temporally and spa-tially controlled conditional knock-outswere much awaited. Mantamadiotis et al.(2002) took advantage of the specific pro-moter driven Cre mouse technology andthe Cre/loxP system to produce severalcell lineage-restricted and temporallycontrolledCreb knock-outmice. In one ofthose mouse lines, CrebNescre, Creb dele-tion was restricted to neuronal and glialprogenitor cells at E16.5 and onward. Thismouse was then crossed with a Cremknock-out line to obtain a conditionalCreb, global Crem double-mutant mouse(CrebNescreCrem/). Disruption of bothCreb and Crem should eliminate CREB/ATF family functions in the nervous sys-tem, since ATF-1 is not normally ex-pressed in brain and was not upregulatedin the Creb knock-outs. CrebNescreCrem/mice died perinatally, because of milksuckling inability. Perinatal immunohis-tochemical analysis revealed that the dou-ble mutant displayed drastic loss of neu-rons throughout the brain with enlargedventricles, attributable to increased neu-ronal apoptosis rather than reduced pro-genitor proliferation.Mantamadiotis et al. (2002) alsoproduced Creb/Crem knock-out micewith a late onset of CREB loss(CrebCamkcre4Crem/) to investigate thefunction of CREB/CREM in adult neu-rons. This mouse exhibited progressiveneuronal loss in hippocampus CA1, den-tate gyrus, and dorsolateral striatum.This severe neurodegeneration pheno-type is consistent with a role of CREB ingrowth factor-dependent survival origi-nally identified in sympathetic neurons byRiccio et al. (1999). However, whereas thegrowth factor-dependent survival in-volves expression of Bcl2, an anti-apoptotic gene, the gross neurodegenera-tion phenotype seen inCrebNescreCrem/mice and region-specific neurodegenera-tion in CrebCamkcre4Crem/mice did notappear to be caused by misregulation ofReceived March 18, 2009; revised April 9, 2009; accepted April 13, 2009.M.N. is supported by a postdoctoral fellowship from the Japan Societyfor the Promotion of Science. I thank Dr. Haruhiko Bito for invaluable com-ments and encouragements.Correspondence should be addressed to Mio Nonaka, Department ofNeurochemistry, Graduate School of Medicine, University of Tokyo, 7-3-1Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail: nonaka@m.u-tokyo.ac.jp.DOI:10.1523/JNEUROSCI.1309-09.2009Copyright©2009SocietyforNeuroscience 0270-6474/09/296389-03$15.00/0The Journal of Neuroscience, May 20, 2009 • 29(20):6389–6391 • 6389the antiapoptotic and proapoptotic Bcl2family (Mantamadiotis et al., 2002). It isnoteworthy that such neurodegenerationwas only present in the Creb/Crem doubleknock-outs and not identified in eitherCreb or Crem single knock-outs, an issuediscussed later in this article.Aguado et al. (2009) used theCrebNescreCrem/ mice described aboveand focused on prenatal synaptogenesis, aprocess that had not been extensively ex-plored. The authors expected that synapsedensity would be decreased, becauseCREB activitywas previously shown to in-crease spine density (Murphy and Segal,1997). A careful electron microscopicstudy was performed, and synaptic con-tacts were quantified in E18 embryos ofcontrol, Creb/Crem single knock-outs,andCrebNescreCrem/mice, in two layersof the hippocampus where pyramidalneuron receive dense inputs. Contrary toexpectations, however, synaptic densityincreased rather than decreased in thehippocampus of double-mutant com-pared with wild-type mice [Aguado et al.(2009), their Fig. 1].Creb and Crem singlemutants also displayed a significant butsmaller increase. No changes in the overallstructure of synapses were discernible byelectron microscopy.A second intriguing phenotype was re-vealed when spontaneous activity of hip-pocampal neurons was examined in slicesusing a calcium dye, fura-2. In mutantslices, the fraction of active cells was sig-nificantly larger, and the frequency andsynchrony of spontaneous activity washigher [Aguado et al. (2009), their Fig. 2],in accordance with the increased synapticcontacts. From these data, the authorsconcluded that CREB is a negative reg-ulator for synaptogenesis and spontane-ous network activity during prenataldevelopment.This new work sheds light on the crit-ical involvement of CREB in the refine-ment of synaptic connectivity during earlybrain development. Importantly, it re-vealed a strong correlation between out-numbered synapses and strengthenedsynchrony. However, at the stage exam-ined, CrebNescreCrem/ mice alreadysuffered increased apoptosis in the hip-pocampus, which started as early as E16.5(Mantamadiotis et al., 2002). Therefore,although the information on neuronaldensity was not provided, it is possiblethat the increased synaptogenesis was asecondary homeostatic effect to compen-sate for neuronal loss, which also mayhave triggered enhanced network activity.To address these issues, future workshould investigate whether enhancedCREB activity during development sup-presses synaptogenesis and network cor-relation, and a temporally restricted res-cue experiment should be attempted onthe double knock-out background.What is the source for the nonevokedcalcium rise measured by Aguado et al.(2009)? Synchronous activity in develop-ing neurons is believed to help build neu-ral networks, although its origin is notfully understood. With pharmacologicalassays, the authors showed that the spon-taneous activity depended mainly on ex-tracellular Ca2 and that GABAA receptorand glutamate receptors were partially(60%) involved [Aguado et al. (2009),their Fig. 3]. Interestingly, both GABAAreceptor and glutamate receptor antago-nists abrogated network activity correla-tion, indicating that excitatory GABA in-put and glutamate input are bothimportant for circuit refinement. The in-creased activity inCrebNescreCrem/ hip-pocampus also essentially depended onextracellular Ca2 and involved GABAAand glutamate receptors, the expressionlevels of which were not altered. Thus, it islikely that increased innervation is themain cause for the enhanced activity.However, it still remains to be determinedwhether the lack of CREB/CREM raisedthe activity and synchrony of immatureneurons via solely trans-synaptic mecha-nisms or multiple mechanisms involvingintracellular Ca2 mobilization or otherCa2 sources such as gap junctions.Aguado et al. (2009) have presentedsituations in which CREB/ATF familymembers do not fully compensate foreach other’s loss: although Creb or Cremsingle mutants did not display increasedapoptosis or progressive neuronal deathas in the double mutant, single Creb orCrem mutants have intermediate pheno-types for enhanced prenatal synaptogen-esis and spontaneous network activity.This implies that CREB and CREM canfully compensate for survival and neuro-degeneration, but their functions on syn-aptogenesis and spontaneous network ac-tivitymay not be completely redundant orcould have dosage dependency.The enhanced synaptogenesis and spon-taneous activity in CrebNescreCrem/micerevealed by Aguado et al. (2009) is surpris-ing given that CREB is widely thought tomediate calcium- and cAMP-dependentgene expression to strengthenneuronal net-work in long-term potentiation, learning,and memory. Several studies have shown acorrelation between increased CREB activ-ity and enhanced synaptogenesis in matureneurons (MurphyandSegal, 1997).Theun-expectednegative regulationbyCREBdem-onstrated here could in part be explained bya difference in developmental stages. E18 iswhen weak spontaneous activities prunesynaptic connections before receivingexternal inputs. During the first or secondweeks after birth, as themice receive sensoryinputs, hippocampal pyramidal neuronsTable 1. A brief summary of Creb and/or Crem knock-out miceKnock-outCREB/ATF familyexpressed in brain Conditional expression ViabilityMajor phenotypes in the nervoussystem ReferencesCreb1 CREB, CREM Viable to adulthood No gross abnormality of development;deficient long-termmemoryHummler et al., 1994Bourtchuladze et al., 1994Blendy et al., 1996bCreb1/ CREM Perinatal death Enlarged ventricles; reducedcommissuresRudolph et al., 1998Crem/ CREB Viable to adulthood Circadian rhythm abnormalities; loweranxiety levelsNantel et al., 1996Blendy et al., 1996aMaldonado et al., 1999CrebNescre Crem/ Developmental (E16.5 andonward) in neuronal andglial progenitorsPerinatal death Progressive neurodegeneration in allareas of the brainMantamadiotis et al., 2002Aguado et al., 2009CrebCamkcre4 Crem/ Postnatal in forebrainregionsViable to adulthood Progressive neurodegeneration inhippocampus and striatumMantamadiotis et al., 20026390 • J. Neurosci., May 20, 2009 • 29(20):6389–6391 Nonaka • Journal Clubundergo drastic changes. GABA switchesfrom excitation to inhibition, axons anddendrites elaborate to form numerous syn-apses, and receptors and channels alter theirproperties by exchanging subunits and/orbeing escorted by scaffolds (Tyzio et al.,1999; Sans et al., 2000). Given such drastictransitions, it is not inconceivable, yet stillremarkable, that the polarity of CREB ac-tion is subject to a complete conversion,from negative to positive. Another possibleinterpretation is that CREB is involved inthe sculpting phase, after the initial massivesynaptogenesis during development. Theauthors did not determine whether the in-creased synaptic terminals were active/silent, glutamatergic/GABAergic, or sym-metric/asymmetric. Marie et al. (2005) pre-viously addressed this issue in mature hip-pocampal neurons, by forced expression ofconstitutively activeCREB, and showed thatthis manipulation resulted in increasedspine density butwith thenet increase beingrestricted to NMDA receptor-only silentsynapses.What is themechanism underlying theopposite effects of CREB in different con-texts? Numerous CREB target genes havebeen proposed, and it is very likely thatdifferent subsets of these target genes areupregulated under each context. The out-standing question is how this can beachieved downstream of a single factor.First, active CREB is believed to form alarge protein complex and is accompa-nied by many other cofactors including arecently identified coactivator (Li et al.,2009); the combination of coactivatorsmay help CREB differentially activateCRE-containing promoters. Second,CREB not only forms homodimers butcan heterodimerize with CREM andATF-1. The significance and activities ofthese heteromers are not well known, butthey might significantly contribute to in-crease the repertoire of CREB function.Third, it has recently been revealed thatthe promoters of immediate early genesoften contain more than two cis-regulatory elements in close proximity toeach other, which potentially enableshigher-order regulation by crosstalk withother transcriptional factors respondingto the same stimuli (Kawashima et al.,2009). Finally, many CREB kinases havebeen identified. The activation profile ofthese upstream kinases may differentiallygovern the ultimate outcomes. Future de-tailed studies on the individual CREB tar-get promoters, CREB coactivators, anddownstream gene expression profilesshould clarify the mechanisms for thedual-function of CREB in neurons andprovide in-depth insights on the com-plexity and the functional richness ofphysiological events regulated by CREBand related transcription factors.ReferencesAguado F, Díaz-Ruiz C, Parlato R, Martínez A,Carmona MA, Bleckmann S, Uren˜a JM, Bur-gaya F, del Río JA, Schu¨tz G, Soriano E (2009)The CREB/CREM transcription factors nega-tively regulate early synaptogenesis andspontaneous network activity. J Neurosci29:328–333.Blendy JA, Kaestner KH, Weinbauer GF, Ni-eschlag E, Schu¨tz G (1996a) Severe impair-ment of spermatogenesis in mice lacking theCREM gene. Nature 380:162–165.Blendy JA, Kaestner KH, Schmid W, Gass P,Schutz G (1996b) Targeting of the CREBgene leads to up-regulation of a novel CREBmRNA isoform. EMBO J 15:1098–1106.Bourtchuladze R, Frenguelli B, Blendy J, Cioffi D,Schutz G, Silva AJ (1994) Deficient long-term memory in mice with a targeted muta-tion of the cAMP-responsive element-bindingprotein. Cell 79:59–68.Hummler E, Cole TJ, Blendy JA, Ganss R, AguzziA, Schmid W, Beermann F, Schu¨tz G (1994)Targeted mutation of the CREB gene: com-pensation within the CREB/ATF family oftranscription factors. Proc Natl Acad SciU S A 91:5647–5651.Kawashima T, Okuno H, Nonaka M, Adachi-Morishima A, Kyo N, Okamura M,Takemoto-Kimura S, Worley PF, Bito H(2009) Synaptic activity-responsive elementin the Arc/Arg3.1 promoter essential forsynapse-to-nucleus signaling in activatedneurons. Proc Natl Acad Sci U S A106:316–321.Li S, Zhang C, Takemori H, Zhou Y, Xiong ZQ(2009) TORC1 regulates activity-dependentCREB-target gene transcription and dendriticgrowth of developing cortical neurons. J Neu-rosci 29:2334–2343.Maldonado R, Smadja C, Mazzucchelli C,Sassone-Corsi P, Mazucchelli C (1999) Al-tered emotional and locomotor responses inmice deficient in the transcription factorCREM. Proc Natl Acad Sci U S A96:14094–14099.Mantamadiotis T, Lemberger T, Bleckmann SC,Kern H, Kretz O, Martin Villalba A, TroncheF, Kellendonk C, Gau D, Kapfhammer J, OttoC, Schmid W, Schu¨tz G (2002) Disruptionof CREB function in brain leads to neurode-generation. Nat Genet 31:47–54.Marie H,MorishitaW, Yu X, Calakos N,MalenkaRC (2005) Generation of silent synapses byacute in vivo expression of CaMKIV andCREB. Neuron 45:741–752.Murphy DD, Segal M (1997) Morphologicalplasticity of dendritic spines in central neu-rons is mediated by activation of cAMP re-sponse element binding protein. Proc NatlAcad Sci U S A 94:1482–1487.Nantel F, Monaco L, Foulkes NS, Masquilier D,LeMeur M, Henrikse´n K, Dierich A, ParvinenM, Sassone-Corsi P (1996) Spermiogenesisdeficiency and germ-cell apoptosis in CREM-mutant mice. Nature 380:159–162.Riccio A, Ahn S, Davenport CM, Blendy JA, GintyDD (1999) Mediation by a CREB familytranscription factor of NGF-dependent sur-vival of sympathetic neurons. Science286:2358–2361.Rudolph D, Tafuri A, Gass P, Ha¨mmerling GJ,Arnold B, Schu¨tz G (1998) Impaired fetal Tcell development and perinatal lethality inmice lacking the cAMP response elementbinding protein. Proc Natl Acad Sci U S A95:4481–4486.Sans N, Petralia RS, Wang YX, Blahos J 2nd, HellJW, Wenthold RJ (2000) A developmentalchange in NMDA receptor-associated pro-teins at hippocampal synapses. J Neurosci20:1260–1271.Shaywitz AJ, Greenberg ME (1999) CREB: astimulus-induced transcription factor acti-vated by a diverse array of extracellular signals.Annu Rev Biochem 68:821–861.Tyzio R, Represa A, Jorquera I, Ben-Ari Y, GozlanH, Aniksztejn L (1999) The establishment ofGABAergic and glutamatergic synapses onCA1 pyramidal neurons is sequential and cor-relates with the development of the apicaldendrite. J Neurosci 19:10372–10382.Nonaka • Journal Club J. Neurosci., May 20, 2009 • 29(20):6389–6391 • 6391

A Janus-like role of CREB protein:enhancement of synaptic property in mature neurons and suppression of synaptogenesis and reduced network synchrony in early development

A Janus-like role of CREB protein:enhancement of synaptic property in mature neurons and suppression of synaptogenesis and reduced network synchrony in early development

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