Does cAMP Response Element-Binding Protein Have a Pivotal Role in Hippocampal Synaptic Plasticity and Hippocampus-Dependent Memory?

Previous studies addressing the role of the transcription factor cAMP response element-binding protein (CREB) in mammalian long-term synaptic plasticity and memory by gene targeting were compromised by incomplete deletion of the CREB isoforms. Therefore, we generated conditional knock-out strains with a marked reduction or complete deletion of all CREB isoforms in the hippocampus. In these strains, no deficits could be detected in lasting forms of hippocampal long-term potentiation (LTP) and long-term depression (LTD). When tested for hippocampus-dependent learning, mutants showed normal context-dependent fear conditioning. Water maze learning was impaired during the early stages, but many mutants showed satisfactory scores in probe trials thought to measure hippocampus-dependent spatial memory. However, conditioned taste aversion learning, a putatively hippocampus-independent memory test, was markedly impaired. Our data indicate that in the adult mouse brain, loss of CREB neither prevents learning nor substantially affects performance in some hippocampus-dependent tasks. Furthermore, it spares LTP and LTD in paradigms that are sensitive enough to detect deficits in other mutants. This implies either a species-specific or regionally restricted role of CREB in the brain and/or a compensatory upregulation of the cAMP response element modulator (CREM) and other as yet unidentified transcription factors.

[1]  D. Ginty,et al.  Function and Regulation of CREB Family Transcription Factors in the Nervous System , 2002, Neuron.

[2]  H. Lipp,et al.  Dissecting the Behaviour of Transgenic Mice: Is it the Mutation, the Genetic Background, or the Environment? , 2000, Experimental physiology.

[3]  J. Blendy,et al.  Activating Transcription Factor 1 and CREB Are Important for Cell Survival during Early Mouse Development , 2002, Molecular and Cellular Biology.

[4]  O. Kretz,et al.  Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety , 1999, Nature Genetics.

[5]  Wolfgang Schmid,et al.  Targeted mutation of the CREB gene: compensation within the CREB/ATF family of transcription factors. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[6]  B. Agranoff,et al.  Chemical studies on memory fixation in goldfish. , 1966, Brain research.

[7]  M. Escobar,et al.  Long-term potentiation in the insular cortex enhances conditioned taste aversion retention , 2000, Brain Research.

[8]  Satoshi Kida,et al.  CREB required for the stability of new and reactivated fear memories , 2002, Nature Neuroscience.

[9]  Eric R. Kandel,et al.  Reversible Inhibition of CREB/ATF Transcription Factors in Region CA1 of the Dorsal Hippocampus Disrupts Hippocampus-Dependent Spatial Memory , 2002, Neuron.

[10]  X. Chen,et al.  Hippocampal CRE-mediated gene expression is required for contextual memory formation , 2002, Nature Neuroscience.

[11]  D. Linden,et al.  A Late Phase of Cerebellar Long-Term Depression Requires Activation of CaMKIV and CREB , 1999, Neuron.

[12]  David P Wolfer,et al.  Genetically modified mice and cognition , 1998, Current Opinion in Neurobiology.

[13]  Marc Montminy,et al.  Transcriptional regulation by the phosphorylation-dependent factor CREB , 2001, Nature Reviews Molecular Cell Biology.

[14]  Hans-Peter Lipp,et al.  Extended analysis of path data from mutant mice using the public domain software Wintrack , 2001, Physiology & Behavior.

[15]  Joseph E LeDoux,et al.  Memory consolidation for contextual and auditory fear conditioning is dependent on protein synthesis, PKA, and MAP kinase. , 1999, Learning & memory.

[16]  E. Kandel,et al.  The past, the future and the biology of memory storage. , 1999, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[17]  H S Pennypacker,et al.  On Behavioral Analysis , 1981, The Behavior analyst.

[18]  Ted Abel,et al.  Behavioral analysis of CREB αΔ mutation on a B6/129 F1 hybrid background , 2002 .

[19]  A. Konnerth,et al.  Impairment of Mossy Fiber Long-Term Potentiation and Associative Learning in Pituitary Adenylate Cyclase Activating Polypeptide Type I Receptor-Deficient Mice , 2001, The Journal of Neuroscience.

[20]  P. Gass,et al.  Impaired fetal T cell development and perinatal lethality in mice lacking the cAMP response element binding protein. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[21]  U. Frey,et al.  Deficits in memory tasks of mice with CREB mutations depend on gene dosage. , 1998, Learning & memory.

[22]  M. Fendt,et al.  The neuroanatomical and neurochemical basis of conditioned fear , 1999, Neuroscience & Biobehavioral Reviews.

[23]  U. Frey,et al.  Anisomycin, an inhibitor of protein synthesis, blocks late phases of LTP phenomena in the hippocampal CA1 region in vitro , 1988, Brain Research.

[24]  W. Schmid,et al.  Targeting of the CREB gene leads to up‐regulation of a novel CREB mRNA isoform. , 1996, The EMBO journal.

[25]  H. Lipp,et al.  Hippocampal mossy fibers and swimming navigation learning in two vole species occupying different habitats , 2000, Hippocampus.

[26]  M. Krug,et al.  Anisomycin blocks the late phase of long-term potentiation in the dentate gyrus of freely moving rats , 1984, Brain Research Bulletin.

[27]  M. Swank.  Phosphorylation of MAP kinase and CREB in mouse cortex and amygdala during taste aversion learning , 2000, NeuroReport.

[28]  W. Quinn,et al.  Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila , 1994, Cell.

[29]  P. Angrand,et al.  Regulation of Cre recombinase activity by the synthetic steroid RU 486. , 1996, Nucleic acids research.

[30]  S. R. Datta,et al.  Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. , 1999, Science.

[31]  Alcino J. Silva,et al.  CREB and memory. , 1998, Annual review of neuroscience.

[32]  Robert C. Malenka,et al.  Synaptic plasticity in the hippocampus: LTP and LTD , 1994, Cell.

[33]  F. Tronche,et al.  PCR-based strategy for genotyping mice and ES cells harboring loxP sites. , 1998, BioTechniques.

[34]  J L McGaugh,et al.  Antisense oligodeoxynucleotide-mediated disruption of hippocampal cAMP response element binding protein levels impairs consolidation of memory for water maze training. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Wolfgang Schmid,et al.  Disruption of CREB function in brain leads to neurodegeneration , 2002, Nature Genetics.

[36]  Alcino J. Silva,et al.  Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein , 1994, Cell.

[37]  M. Escobar,et al.  The NMDA receptor antagonist CPP impairs conditioned taste aversion and insular cortex long-term potentiation in vivo. , 1998, Brain Research.

[38]  D. Storm,et al.  Stimulation of cAMP response element (CRE)-mediated transcription during contextual learning , 1998, Nature Neuroscience.

[39]  K. Deisseroth,et al.  Signaling from Synapse to Nucleus: Postsynaptic CREB Phosphorylation during Multiple Forms of Hippocampal Synaptic Plasticity , 1996, Neuron.

[40]  T. Tully,et al.  CREB as a Memory Modulator: induced expression of a dCREB2 activator isoform enhances long-term memory in drosophila , 1995, Cell.

[41]  Alcino J. Silva,et al.  Spaced training induces normal long-term memory in CREB mutant mice , 1997, Current Biology.

[42]  W Zieglgänsberger,et al.  Synaptic plasticity in the basolateral amygdala in transgenic mice expressing dominant‐negative cAMP response element‐binding protein (CREB) in forebrain , 2000, The European journal of neuroscience.

[43]  Devang Akotia Barbara Barry Bautista Jennifer Natasha Bri Alfa.  Reversible Inhibition of CREB / ATF Transcription Factors in Region CA 1 of the Dorsal Hippocampus Disrupts Hippocampus Dependent Spatial Memory , 2005 .

[44]  G. Wogan.  Review of the toxicology of tamoxifen. , 1997, Seminars in oncology.

[45]  H. Lipp,et al.  Conditioned taste aversion as a learning and memory paradigm , 2001, Behavioural Brain Research.

[46]  Y. Dudai,et al.  cAMP Response Element-Binding Protein in the Amygdala Is Required for Long- but not Short-Term Conditioned Taste Aversion Memory , 1997, The Journal of Neuroscience.

[47]  Mary Chen,et al.  Aplysia CREB2 represses long-term facilitation: Relief of repression converts transient facilitation into long-term functional and structural change , 1995, Cell.