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Deletion of the Coffin–Lowry Syndrome Gene Rsk2 in Mice is Associated With Impaired Spatial Learning and Reduced Control of Exploratory Behavior

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Abstract

Coffin–Lowry Syndrome (CLS) is an X-linked syndromic form of mental retardation associated with skeletal abnormalities. It is caused by mutations of the Rsk2 gene, which encodes a growth factor regulated kinase. Gene deletion studies in mice have shown an essential role for the Rsk2 gene in osteoblast differentiation and function, establishing a causal link between Rsk2 deficiency and skeletal abnormalities of CLS. Although analyses in mice have revealed prominent expression of Rsk2 in brain structures that are essential for learning and memory, evidence at the behavioral level for an involvement of Rsk2 in cognitive function is still lacking. Here, we have examined Rsk2-deficient mice in two extensive batteries of behavioral tests, which were conducted independently in two laboratories in Zurich (Switzerland) and Orsay (France). Despite the known reduction of bone mass, all parameters of motor function were normal, confirming the suitability of Rsk2-deficient mice for behavioral testing. Rsk2-deficient mice showed a mild impairment of spatial working memory, delayed acquisition of a spatial reference memory task and long-term spatial memory deficits. In contrast, associative and recognition memory, as well as the habituation of exploratory activity were normal. Our studies also revealed mild signs of disinhibition in exploratory activity, as well as a difficulty to adapt to new test environments, which likely contributed to the learning impairments displayed by Rsk2-deficient mice. The observed behavioral changes are in line with observations made in other mouse models of human mental retardation and support a role of Rsk2 in cognitive functions.

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References

  • Alarcon JM, Malleret G, Touzani K, Vronskaya S, Ishii S, Kandel ER, Barco A (2004) Chromatin acetylation, memory, and LTP are impaired in CBP (±) mice; a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration. Neuron 42:947–959

    Article  PubMed  CAS  Google Scholar 

  • Atkins CM, Selcher JC, Petraitis JJ, Trzaskos JM, Sweatt JD (1998) The MAPK cascade is required for mammalian associative learning. Nat Neurosci 1:602–609

    Article  PubMed  CAS  Google Scholar 

  • Aylward GP (2002). Cognitive and neuropsychological outcomes: more than IQ scores. Ment Retard Dev Disabil Res Rev 8:234–240

    Article  PubMed  Google Scholar 

  • Bakker CE, Verhehij C, Willemsen R, van der Helm R, Oerlemans F, Vermey M, Bygrave A, Hoogeveen AT, Oostra BA, Reyniers E, et al (1994). Fmr1 knockout mice: a model to study fragile X mental retardation. The Dutch-Belgian Fragile X Consortium. Cell 78:23–33

    Google Scholar 

  • Balschun D, Wolfer DP, Gass P, Mantamadiotis T, Welzl H, Schutz G, Frey JU, Lipp HP (2003) Does cAMP response element-binding protein have a pivotal role in hippocampal synaptic plasticity and hippocampus-dependent memory? J Neurosci 23:6304–6314

    PubMed  CAS  Google Scholar 

  • Bartsch D, Ghirardi M, Skehel PA, Karl KA, Herder SP, Chen M, Bailey CH, Kandel ER (1995) Aplysia CREB2 represses long-term facilitation: relief of repression converts transient facilitation into long-term functional and structural change. Cell 83:979–992

    Article  PubMed  CAS  Google Scholar 

  • Benjamini Y, Drai D, Elmer G, Kafkafi N, Golani I (2001). Controlling the false discovery rate in behavior genetics research. Behav Brain Res 125:279–284

    Article  PubMed  CAS  Google Scholar 

  • Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Royal Stat Soc Ser B 57:289–300

    Google Scholar 

  • Berger S, Wolfer DP, Selbach O, Alter H, Erdmann G, Reichardt HM, Chepkova AN, Welzl H, Haas HL, Lipp HP, Schutz G (2006). Loss of the limbic mineralocorticoid receptor impairs behavioral plasticity. Proc Natl Acad Sci USA 103:195–200

    Article  PubMed  CAS  Google Scholar 

  • Blum S, Moore AN, Adams F, Dash PK (1999). A mitogen-activated protein kinase cascade in the CA1/CA2 subfield of the dorsal hippocampus is essential for long-term spatial memory. Journal of Neurocience 19:3535–3544

    CAS  Google Scholar 

  • Bontekoe CJ, McIlwain KL, Nieuwenhuizen IM, Yuva-Paylor LA, Nellis A, Willemsen R, Fang Z, Kirkpatrick L, Bakker CE, McAninch R, et al (2002) Knockout mouse model for Fxr2: a model for mental retardation. Hum Mol Genet 11:487–498

    Article  PubMed  CAS  Google Scholar 

  • Bourtchuladze R, Frenguelli B, Blendy J, Cioffi D, Schutz G, Silva AJ (1994) Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element binding protein. Cell 79:59–68

    Article  PubMed  CAS  Google Scholar 

  • Bozon B, Davis S, Laroche S (2002) Regulated transcription of the immediate-early gene Zif268: mechanisms and gene dosage-dependent function in synaptic plasticity and memory formation. Hippocampus 12:570–577

    Article  PubMed  CAS  Google Scholar 

  • Bozon B, Kelly A, Josselyn SA, Silva AJ, Davis S, Laroche S (2003) MAPK, CREB and zif268 are all required for the consolidation of recognition memory. Philos Trans R Soc Lond B Biol Sci 358:805–814

    Article  PubMed  CAS  Google Scholar 

  • Brosnan-Watters G, Wozniak DF (1997) A rotating holeboard procedure for testing drug effects on spatial learning and memory in mice. Brain Res Brain Res Protoc 1:331–338

    Article  PubMed  CAS  Google Scholar 

  • Cabib S, Pascucci T, Ventura R, Romano V, Puglisi-Allegra S (2003) The behavioral profile of severe mental retardation in a genetic mouse model of phenylketonuria. Behav Genet 33:301–310

    Article  PubMed  Google Scholar 

  • Chen A, Muzzio IA, Malleret G, Bartsch D, Verbitsky M, Pavlidis P, Yonan AL, Vronskaya S, Grody MB, Cepeda I, et al (2003) Inducible enhancement of memory storage and synaptic plasticity in transgenic mice expressing an inhibitor of ATF4 (CREB-2) and C/EBP proteins. Neuron 39:655–669

    Article  PubMed  CAS  Google Scholar 

  • Chen G, Chen KS, Knox J, Inglis J, Bernard A, Martin SJ, Justice A, McConlogue L, Games D, Freedman SB, Morris RG (2000) A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer’s disease. Nature 408:975–979

    Article  PubMed  CAS  Google Scholar 

  • Chen L, Toth M (2001) Fragile X mice develop sensory hyperreactivity to auditory stimuli. Neuroscience 103:1043–1050

    Article  PubMed  CAS  Google Scholar 

  • Coffin R, Phillips JL, Staples WI, Spector S (1966) Treatment of lead encephalopathy in children. J Pediatr 69:198–206

    Article  PubMed  CAS  Google Scholar 

  • Cohen NR, Taylor JS, Scott LB, Guillery RW, Soriano P, Furley AJ (1998). Errors in corticospinal axon guidance in mice lacking the neural cell adhesion molecule L1. Curr Biol 8:26–33

    Article  PubMed  CAS  Google Scholar 

  • Costa-Mattioli M, Gobert D, Harding H, Herdy B, Azzi M, Bruno M, Bidinosti M, Ben Mamou C, Marcinkiewicz E, Yoshida M, et al (2005) Translational control of hippocampal synaptic plasticity and memory by the eIF2alpha kinase GCN2. Nature 436:1166–1173

    Article  PubMed  CAS  Google Scholar 

  • Crabbe JC, Wahlsten D, Dudek BC (1999) Genetics of mouse behavior: interactions with laboratory environment. Science 284:1670–1672

    Article  PubMed  CAS  Google Scholar 

  • D’Adamo P, Welzl H, Papadimitriou S, Raffaele DB, Tiveron C, Tatangelo L, Pozzi L, Chapman PF, Knevett SG, Ramsay MF, et al (2002) Deletion of the mental retardation gene Gdi1 impairs associative memory and alters social behavior in mice. Hum Mol Genet 11:2567–2580

    Article  PubMed  CAS  Google Scholar 

  • Dahme M, Bartsch U, Martini R, Anliker B, Schachner M, Mantei N (1997) Disruption of the mouse L1 gene leads to malformations of the nervous system. Nat Genet 17:346–349

    Article  PubMed  CAS  Google Scholar 

  • Darragh J, Soloaga A, Beardmore VA, Wingate AD, Wiggin GR, Peggie M, Arthur JS (2005) MSKs are required for the transcription of the nuclear orphan receptors Nur77, Nurr1 and Nor1 downstream of MAPK signalling. Biochem J 390:749–759

    Article  PubMed  CAS  Google Scholar 

  • Davis RJ (2000) Signal transduction by the JNK group of MAP kinases. Cell 103:239–252

    Article  PubMed  CAS  Google Scholar 

  • Davis S, Laroche S (2006). Mitogen-activated protein kinase/extracellular regulated kinase signalling and memory stabilization: a review. Genes Brain Behav 5(Suppl 2):61–72

    Article  PubMed  CAS  Google Scholar 

  • De Cesare D, Jacquot S, Hanauer A, Sassone-Corsi P (1998) Rsk-2 activity is necessary for epidermal growth factor-induced phosphorylation of CREB protein and transcription of c-fos gene. Proc Natl Acad Sci USA 95:12202–12207

    Article  PubMed  Google Scholar 

  • Delaunoy J, Abidi F, Zeniou M, Jacquot S, Merienne K, Pannetier S, Schmitt M, Schwartz C, Hanauer A (2001) Mutations in the X-linked RSK2 gene (RPS6KA3) in patients with Coffin–Lowry syndrome. Hum Mutat 17:103–116

    Article  PubMed  CAS  Google Scholar 

  • Drai D, Golani I (2001). SEE: a tool for the visualization and analysis of rodent exploratory behavior. Neurosci Biobehav Rev 25:409–426

    Article  PubMed  CAS  Google Scholar 

  • Dufresne SD, Bjorbaek C, El-Haschimi K, Zhao Y, Aschenbach WG, Moller DE, Goodyear LJ (2001). Altered extracellular signal-regulated kinase signaling and glycogen metabolism in skeletal muscle from p90 ribosomal S6 kinase 2 knockout mice. Mol Cell Biol 21:81–87

    Article  PubMed  CAS  Google Scholar 

  • Dulawa SC, Grandy DK, Low MJ, Paulus MP, Geyer MA (1999). Dopamine D4 receptor-knock-Out mice exhibit reduced exploration of novel stimuli. J Neurosci 19:9550–9556

    PubMed  CAS  Google Scholar 

  • El-Haschimi K, Dufresne SD, Hirshman MF, Flier JS, Goodyear LJ, Bjorbaek C (2003) Insulin resistance and lipodystrophy in mice lacking ribosomal S6 kinase 2. Diabetes 52:1340–1346

    Article  PubMed  CAS  Google Scholar 

  • English JD, Sweatt JD (1997) A requirement for the mitogen-activated protein kinase cascade in hippocampal long-term potentiation. J Biol Chem 272:19103–19106

    Article  PubMed  CAS  Google Scholar 

  • Fransen E, Dhooge R, Vancamp G, Verhoye M, Sijbers J, Reyniers E, Soriano P, Kamiguchi H, Willemsen R, Koekkoek SKE et al (1998) L1 knockout mice show dilated ventricles, vermis hypoplasia and impaired exploration patterns. Hum Mol Genet 7:999–1009

    Article  PubMed  CAS  Google Scholar 

  • Frodin M, Gammeltoft S (1999) Role and regulation of 90 kDa ribosomal S6 kinase (RSK) in signal transduction. Mol Cell Endocrinol 151:65–77

    Article  PubMed  CAS  Google Scholar 

  • Gass P, Wolfer DP, Balschun D, Rudolph D, Frey JU, Lipp HP, Schutz G (1998) Deficits in memory tasks of mice with CREB mutations depend on gene dosage. Learn Mem 5:274–288

    PubMed  CAS  Google Scholar 

  • Gu Y, McIlwain KL, Weeber EJ, Yamagata T, Xu B, Antalffy BA, Reyes C, Yuva-Paylor L, Armstrong D, Zoghbi H, et al (2002) Impaired conditioned fear and enhanced long-term potentiation in Fmr2 knock-out mice. J Neurosci 22:2753–2763

    PubMed  CAS  Google Scholar 

  • Guy J, Hendrich B, Holmes M, Martin JE, Bird A (2001) A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat Genet 27:322–326

    Article  PubMed  CAS  Google Scholar 

  • Hanauer A, Alembik Y, Gilgenkrantz S, Mujica P, Nivelon-Chevallier A, Pembrey ME, Young ID, Mandel JL (1988) Probable localisation of the Coffin–Lowry locus in Xp22.2-p22.1 by multipoint linkage analysis. Am J Med Genet 30:523–530

    Article  PubMed  CAS  Google Scholar 

  • Hanauer A, Young ID (2002) Coffin–Lowry syndrome: clinical and molecular features. J Med Genet 39:705–713

    Article  PubMed  CAS  Google Scholar 

  • Harum KH, Alemi L, Johnston MV (2001) Cognitive impairment in Coffin–Lowry syndrome correlates with reduced RSK2 activation. Neurology 56:207–214

    PubMed  CAS  Google Scholar 

  • Hodges H (1996) Maze procedures: the radial-arm and water maze compared. Brain Res Cogn Brain Res 3:167–181

    Article  PubMed  CAS  Google Scholar 

  • Irintchev A, Koch M, Needham LK, Maness P, Schachner M (2004). Impairment of sensorimotor gating in mice deficient in the cell adhesion molecule L1 or its close homologue, CHL1. Brain Res 1029:131–134

    Article  PubMed  CAS  Google Scholar 

  • Ishizaki H, Miyoshi J, Kamiya H, Togawa A, Tanaka M, Sasaki T, Endo K, Mizoguchi A, Ozawa S, Takai Y (2000) Role of rab GDP dissociation inhibitor alpha in regulating plasticity of hippocampal neurotransmission. Proc Natl Acad Sci USA 97:11587–11592

    Article  PubMed  CAS  Google Scholar 

  • Jacquot S, Merienne K, De Cesare D, Pannetier S, Mandel JL, Sassone-Corsi P, Hanauer A (1998) Mutation analysis of the RSK2 gene in Coffin–Lowry patients: extensive allelic heterogeneity and a high rate of de novo mutations. Am J Hum Genet 63:1631–1640

    Article  PubMed  CAS  Google Scholar 

  • Kafkafi N, Lipkind D, Benjamini Y, Mayo CL, Elmer GI, Golani I (2003a) SEE locomotor behavior test discriminates C57BL/6J and DBA/2J mouse inbred strains across laboratories and protocol conditions. Behav Neurosci 117:464–477

    Article  Google Scholar 

  • Kafkafi N, Pagis M, Lipkind D, Mayo CL, Bemjamini Y, Golani I, Elmer GI (2003b) Darting behavior: a quantitative movement pattern designed for discrimination and replicability in mouse locomotor behavior. Behav Brain Res 142:193–205

    Article  Google Scholar 

  • Kelly A, Laroche S, Davis S (2003) Activation of mitogen-activated protein kinase/extracellular signal-regulated kinase in hippocampal circuitry is required for consolidation and reconsolidation of recognition memory. J Neurosci 23:5354–5360

    PubMed  CAS  Google Scholar 

  • Keren G, Lewis C (1979) Partial omega squared for ANOVA designs. Educ Psychol Measur 39:119–128

    Article  Google Scholar 

  • Kida S, Josselyn SA, de Ortiz SP, Kogan JH, Chevere I, Masushige S, Silva AJ (2002) CREB required for the stability of new and reactivated fear memories. Nat Neurosci 5:348–355

    Article  PubMed  CAS  Google Scholar 

  • Kogan JH, Frankland PW, Blendy JA, Coblentz J, Marowitz Z, Schutz G, Silva AJ (1997) Spaced training induces normal long-term memory in CREB mutant mice. Curr Biol 7:1–11

    Article  PubMed  CAS  Google Scholar 

  • Konig M, Zimmer AM, Steiner H, Holmes PV, Crawley JN, Brownstein MJ, Zimmer A (1996) Pain responses, anxiety and aggression in mice deficient in pre-proenkephalin. Nature 383:535–538

    Article  PubMed  CAS  Google Scholar 

  • Korzus E, Rosenfeld MG, Mayford M (2004) CBP histone acetyltransferase activity is a critical component of memory consolidation. Neuron 42:961–972

    Article  PubMed  CAS  Google Scholar 

  • Kutsche K, Yntema H, Brandt A, Jantke I, Nothwang HG, Orth U, Boavida MG, David D, Chelly J, Fryns JP, et al (2000) Mutations in ARHGEF6, encoding a guanine nucleotide exchange factor for Rho GTPases, in patients with X-linked mental retardation. Nat Genet 26:247–250

    Article  PubMed  CAS  Google Scholar 

  • Levenson JM, O’Riordan KJ, Brown KD, Trinh MA, Molfese DL, Sweatt JD (2004) Regulation of histone acetylation during memory formation in the hippocampus. J Biol Chem 279:40545–40559

    Article  PubMed  CAS  Google Scholar 

  • Lewejohann L, Reinhard C, Schrewe A, Brandewiede J, Haemisch A, Gortz N, Schachner M, Sachser N (2006) Environmental bias? Effects of housing conditions, laboratory environment and experimenter on behavioral tests. Genes Brain Behav 5:64–72

    Article  PubMed  CAS  Google Scholar 

  • Lipp HP, Wolfer DP (1998) Genetically modified mice and cognition. Curr Opin Neurobiol 8:272–280

    Article  PubMed  CAS  Google Scholar 

  • Lowry B, Miller JR, Fraser FC (1971) A new dominant gene mental retardation syndrome. Association with small stature, tapering fingers, characteristic facies, and possible hydrocephalus. Am J Dis Child 121:496–500

    PubMed  CAS  Google Scholar 

  • Madani R, Kozlov S, Akhmedov A, Cinelli P, Kinter J, Lipp HP, Sonderegger P, Wolfer DP (2003) Impaired explorative behavior and neophobia in genetically modified mice lacking or overexpressing the extracellular serine protease inhibitor neuroserpin. MolCell Neurosci 23:473–494

    Article  CAS  Google Scholar 

  • McDonald JD, Bode VC, Dove WF, Shedlovsky A (1990) Pahhph-5: a mouse mutant deficient in phenylalanine hydroxylase. Proc Natl Acad Sci USA 87:1965–1967

    Article  PubMed  CAS  Google Scholar 

  • Mineur YS, Huynh LX, Crusio WE (2006) Social behavior deficits in the Fmr1 mutant mouse. Behav Brain Res 168:172–175

    Article  PubMed  CAS  Google Scholar 

  • Mineur YS, Sluyter F, de Wit S, Oostra BA, Crusio WE (2002) Behavioral and neuroanatomical characterization of the Fmr1 knockout mouse. Hippocampus 12:39–46

    Article  PubMed  Google Scholar 

  • Mohajeri MH, Madani R, Saini K, Lipp HP, Nitsch RM, Wolfer DP (2004) The impact of genetic background on neurodegeneration and behavior in seizured mice. Genes Brain Behav 3:228–239

    Article  PubMed  CAS  Google Scholar 

  • Moretti P, Levenson JM, Battaglia F, Atkinson R, Teague R, Antalffy B, Armstrong D, Arancio O, Sweatt JD, Zoghbi HY (2006). Learning and memory and synaptic plasticity are impaired in a mouse model of Rett syndrome. J Neurosci 26:319–327

    Article  PubMed  CAS  Google Scholar 

  • Nielsen DM, Derber WJ, McClellan DA, Crnic LS (2002) Alterations in the auditory startle response in Fmr1 targeted mutant mouse models of fragile X syndrome. Brain Res 927:8–17

    Article  PubMed  CAS  Google Scholar 

  • Peier AM, McIlwain KL, Kenneson A, Warren ST, Paylor R, Nelson DL (2000) (Over)correction of FMR1 deficiency with YAC transgenics: behavioral and physical features. Hum Mol Genet 9:1145–1159

    Article  PubMed  CAS  Google Scholar 

  • Sassone-Corsi P, Mizzen CA, Cheung P, Crosio C, Monaco L, Jacquot S, Hanauer A, Allis CD (1999). Requirement of Rsk-2 for epidermal growth factor-activated phosphorylation of histone H3. Science 285:886–891

    Article  PubMed  CAS  Google Scholar 

  • Schafe GE, Atkins CM, Swank MW, Bauer EP, Sweatt JD, LeDoux JE (2000) Activation of ERK/MAP kinase in the amygdala Is required for memory consolidation of pavlovian fear conditioning. J Neurosci 20:8177–8187

    PubMed  CAS  Google Scholar 

  • Schalock RL, Stark JA, Snell ME, Coulter DL, Polloway EA, Luckasson R, Reiss S, Spitalnik DM (1994). The changing conception of mental retardation: implications for the field. Ment Retard 32:181–193

    PubMed  CAS  Google Scholar 

  • Selcher JC, Atkins CM, Trzaskos JM, Paylor R, Sweatt JD (1999) A necessity for MAP kinase activation in mammalian spatial learning. LearnMem 6:478–490

    CAS  Google Scholar 

  • Silva AJ, Frankland PW, Marowitz Z, Friedman E, Lazlo G, Cioffi D, Jacks T, Bourtchuladze R (1997) A mouse model for the learning and memory deficits associated with neurofibromatosis type 1. NatGenet 15:281–284

    CAS  Google Scholar 

  • Sweatt JD (2001) The neuronal MAP kinase cascade: a biochemical signal integration system subserving synaptic plasticity and memory. J Neurochem 76:1–10

    Article  PubMed  CAS  Google Scholar 

  • Sweatt JD (2004) Mitogen-activated protein kinases in synaptic plasticity and memory. Curr Opin Neurobiol 14:311–317

    Article  PubMed  CAS  Google Scholar 

  • Touraine RL, Zeniou M, Hanauer A (2002) A syndromic form of X-linked mental retardation: the Coffin–Lowry syndrome. Eur J Pediatr 161:179–187

    Article  PubMed  CAS  Google Scholar 

  • Trivier E, De Cesare D, Jacquot S, Pannetier S, Zackai E, Young I, Mandel JL, Sassone-Corsi P, Hanauer A (1996) Mutations in the kinase Rsk-2 associated with Coffin–Lowry syndrome. Nature 384:567–570

    Article  PubMed  CAS  Google Scholar 

  • Vaillend C, Billard JM, Laroche S (2004) Impaired long-term spatial and recognition memory and enhanced CA1 hippocampal LTP in the dystrophin-deficient Dmd(mdx) mouse. Neurobiol Dis 17:10–20

    Article  PubMed  CAS  Google Scholar 

  • Wiggin GR, Soloaga A, Foster JM, Murray-Tait V, Cohen P, Arthur JS (2002) MSK1 and MSK2 are required for the mitogen- and stress-induced phosphorylation of CREB and ATF1 in fibroblasts. Mol Cell Biol 22:2871–2881

    Article  PubMed  CAS  Google Scholar 

  • Wolfer DP, Kuchenbecker K, Prut L, Neuhausser-Wespy F, Kutsche K, Lipp, H P (2005) Impaired behavioral control and altered processing of spatial information in mice deficient for the X-chromosomal mental retardation gene Arhgef6. Society for Neuroscience 35th Meeting

  • Wolfer DP, Litvin O, Morf S, Nitsch RM, Lipp HP, Wurbel H (2004) Laboratory animal welfare: cage enrichment and mouse behaviour. Nature 432:821–822

    Article  PubMed  CAS  Google Scholar 

  • Wolfer DP, Madani R, Valenti P, Lipp HP (2001) Extended analysis of path data from mutant mice using the public domain software Wintrack. Physiol Behav 73:745–753

    Article  PubMed  CAS  Google Scholar 

  • Wolfer DP, Stagliar-Bozizevic M, Errington ML, Lipp HP (1998). Spatial memory and learning in transgenic mice: fact or artifact?. News Physiol Sci 13:118–123

    PubMed  Google Scholar 

  • Xing J, Ginty DD, Greenberg ME (1996) Coupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. Science 273:959–963

    Article  PubMed  CAS  Google Scholar 

  • Yang X, Matsuda K, Bialek P, Jacquot S, Masuoka HC, Schinke T, Li L, Brancorsini S, Sassone-Corsi P, Townes TM, et al (2004) ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin–Lowry Syndrome. Cell 117:387–398

    Article  PubMed  CAS  Google Scholar 

  • Yin JC, Wallach JS, Del Vecchio M, Wilder EL, Zhou H, Quinn WG, Tully T (1994) Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila. Cell 79:49–58

    Article  PubMed  CAS  Google Scholar 

  • Zagreda L, Goodman J, Druin DP, McDonald D, Diamond A (1999). Cognitive deficits in a genetic mouse model of the most common biochemical cause of human mental retardation. J Neurosci 19:6175–6182

    PubMed  CAS  Google Scholar 

  • Zeniou M, Ding T, Trivier E, Hanauer A (2002) Expression analysis of RSK gene family members: the RSK2 gene, mutated in Coffin–Lowry syndrome, is prominently expressed in brain structures essential for cognitive function and learning. Hum Mol Genet 11:2929–2940

    Article  PubMed  CAS  Google Scholar 

  • Zorner B, Wolfer DP, Brandis D, Kretz O, Zacher C, Madani R, Grunwald I, Lipp HP, Klein R, Henn FA, Gass P (2003) Forebrain-specific trkB-receptor knockout mice: behaviorally more hyperactive than “depressive”. Biol Psychiatry 54:972–982

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the Swiss National Science Foundation and the NCCR “Neural Plasticity and Repair”, and by grants from GIS INSERM “Maladies Rares” and ANR (No. ANR-05-NEUR-005-01) to A.H. and S.L. We thank Inger Drescher and Rosmarie Lang for expert help with the behavioral experiments. We thank Benoit Delatour for the development of home-made programs to analyze behavioral data in Orsay. We are grateful to Solange Pannetier, Nathalie Samson, Sandra Vandergeenst, and Pascale Veyrac for animal care.

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Authors and Affiliations

  1. Laboratoire de Neurobiologie de l’Apprentissage, de la Mémoire et de la Communication CNRS, UMR 8620, Université Paris-Sud, 91405, Orsay, France

    R. Poirier, C. Vaillend, A. A. Soutthiphong, M. Libbey, S. Davis & S. Laroche

  2. Institute of Anatomy, University of Zürich, 190 Winterthurerstrasse, CH-8057, Zurich, Switzerland

    S. Jacquot, H. Welzl, H.-P. Lipp & D. P. Wolfer

  3. Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 67404, Illkirch, France

    A. Hanauer

  4. Department of Biology, ETH Zürich, CH-8092, Zurich, Switzerland

    D. P. Wolfer

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  1. R. Poirier
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Poirier, R., Jacquot, S., Vaillend, C. et al. Deletion of the Coffin–Lowry Syndrome Gene Rsk2 in Mice is Associated With Impaired Spatial Learning and Reduced Control of Exploratory Behavior. Behav Genet 37, 31–50 (2007). https://doi.org/10.1007/s10519-006-9116-1

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