Activation of exchange protein activated by cyclic-AMP enhances long-lasting synaptic potentiation in the hippocampus.

cAMP is a critical second messenger implicated in synaptic plasticity and memory in the mammalian brain. Substantial evidence links increases in intracellular cAMP to activation of cAMP-dependent protein kinase (PKA) and subsequent phosphorylation of downstream effectors (transcription factors, receptors, protein kinases) necessary for long-term potentiation (LTP) of synaptic strength. However, cAMP may also initiate signaling via a guanine nucleotide exchange protein directly activated by cAMP (Epac). The role of Epac in hippocampal synaptic plasticity is unknown. We found that in area CA1 of mouse hippocampal slices, activation of Epac enhances maintenance of LTP without affecting basal synaptic transmission. The persistence of this form of LTP requires extracellular signal-regulated protein kinase (ERK) and new protein synthesis, but not transcription. Because ERK is involved in translational control of long-lasting plasticity and memory, our data suggest that Epac is a crucial link between cAMP and ERK during some forms of protein synthesis-dependent LTP. Activation of Epac represents a novel signaling pathway for rapid regulation of the stability of enduring forms of LTP and, perhaps, of hippocampus- dependent long-term memories.

[1]  S. Tonegawa,et al.  The Essential Role of Hippocampal CA1 NMDA Receptor–Dependent Synaptic Plasticity in Spatial Memory , 1996, Cell.

[2]  Louis J Muglia,et al.  Calcium-Stimulated Adenylyl Cyclase Activity Is Critical for Hippocampus-Dependent Long-Term Memory and Late Phase LTP , 1999, Neuron.

[3]  D. S. Cowen,et al.  Enhanced activation of Akt and extracellular‐regulated kinase pathways by simultaneous occupancy of Gq‐coupled 5‐HT2A receptors and Gs‐coupled 5‐HT7A receptors in PC12 cells , 2005, Journal of neurochemistry.

[4]  S. Shenolikar,et al.  Long-Term Potentiation Induced by θ Frequency Stimulation Is Regulated by a Protein Phosphatase-1-Operated Gate , 2000, The Journal of Neuroscience.

[5]  E. Kandel,et al.  Effects of cAMP simulate a late stage of LTP in hippocampal CA1 neurons. , 1993, Science.

[6]  Eric R Kandel,et al.  ERK Plays a Regulatory Role in Induction of LTP by Theta Frequency Stimulation and Its Modulation by β-Adrenergic Receptors , 1999, Neuron.

[7]  N. Sonenberg,et al.  Regulation of Eukaryotic Initiation Factor 4E by Converging Signaling Pathways during Metabotropic Glutamate Receptor-Dependent Long-Term Depression , 2006, The Journal of Neuroscience.

[8]  E. Hirsch,et al.  The Phenotypic Differentiation of Locus Coeruleus Noradrenergic Neurons Mediated by BDNF is Enhanced by Corticotropin Releasing Factor through the Activation of a cAMP-Dependent Signaling Pathway , 2006 .

[9]  E. Kandel,et al.  A Macromolecular Synthesis-Dependent Late Phase of Long-Term Potentiation Requiring cAMP in the Medial Perforant Pathway of Rat Hippocampal Slices , 1996, The Journal of Neuroscience.

[10]  V. Doyère,et al.  Linear relationship between the maintenance of hippocampal long‐term potentiation and retention of an associative memory , 1992, Hippocampus.

[11]  P. Nguyen,et al.  Regulation of hippocampal synaptic plasticity by cyclic AMP-dependent protein kinases , 2003, Progress in Neurobiology.

[12]  G. Lynch,et al.  A critical level of protein synthesis is required for long‐term potentiation , 1987, Synapse.

[13]  P. Stork,et al.  Rap1-Mediated Activation of Extracellular Signal-Regulated Kinases by Cyclic AMP Is Dependent on the Mode of Rap1 Activation , 2006, Molecular and Cellular Biology.

[14]  S. Shenolikar,et al.  Gating of CaMKII by cAMP-regulated protein phosphatase activity during LTP. , 1998, Science.

[15]  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.

[16]  Hyejin Kang,et al.  Translational Control by MAPK Signaling in Long-Term Synaptic Plasticity and Memory , 2004, Cell.

[17]  E. Kandel,et al.  Requirement of a critical period of transcription for induction of a late phase of LTP. , 1994, Science.

[18]  P. Serrano,et al.  Protein synthesis‐dependent LTP in isolated dendrites of CA1 pyramidal cells , 2005, Hippocampus.

[19]  L. Squire,et al.  Human amnesia and the medial temporal region: enduring memory impairment following a bilateral lesion limited to field CA1 of the hippocampus , 1986, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[20]  T. Bliss,et al.  A synaptic model of memory: long-term potentiation in the hippocampus , 1993, Nature.

[21]  E. Hirsch,et al.  The Phenotypic Differentiation of Locus Ceruleus Noradrenergic Neurons Mediated by Brain-Derived Neurotrophic Factor Is Enhanced by Corticotropin Releasing Factor through the Activation of a cAMP-Dependent Signaling Pathway , 2006, Molecular Pharmacology.

[22]  E. Kandel.  The Molecular Biology of Memory Storage: A Dialogue Between Genes and Synapses , 2001, Science.

[23]  F. Lezoualc’h,et al.  Crosstalk between Rap1 and Rac regulates secretion of sAPPα , 2003, Nature Cell Biology.

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

[25]  T. Soderling,et al.  Calmodulin-dependent Kinase Kinase/calmodulin Kinase I Activity Gates Extracellular-regulated Kinase-dependent Long-term Potentiation Intracellular Ca 2ϩ and Protein Phosphorylation Play Pivotal Roles in Long-term Potentiation (ltp), a Cellular Model of Learning and Memory. Ca 2ϩ Regulates Multiple , 2005 .

[26]  A M Graybiel,et al.  A family of cAMP-binding proteins that directly activate Rap1. , 1998, Science.

[27]  Ravi Iyengar,et al.  Local Protein Synthesis Mediates a Rapid Increase in Dendritic Elongation Factor 1A after Induction of Late Long-Term Potentiation , 2005, The Journal of Neuroscience.

[28]  T. Teyler.  Long-term potentiation and memory. , 1987, International journal of neurology.

[29]  M. Bear,et al.  Chemical Induction of mGluR 5-and Protein Synthesis – Dependent Long-Term Depression in Hippocampal Area CA 1 , 2001 .

[30]  J. Bos,et al.  Epac proteins: multi-purpose cAMP targets. , 2006, Trends in biochemical sciences.

[31]  Peter V. Nguyen,et al.  β-Adrenergic Receptor Activation Facilitates Induction of a Protein Synthesis-Dependent Late Phase of Long-Term Potentiation , 2005, The Journal of Neuroscience.

[32]  D. S. Cowen,et al.  Coupling of neuronal 5‐HT7 receptors to activation of extracellular‐regulated kinase through a protein kinase A‐independent pathway that can utilize Epac , 2003, Journal of neurochemistry.

[33]  E. Schuman,et al.  A Requirement for Local Protein Synthesis in Neurotrophin-Induced Hippocampal Synaptic Plasticity , 1996, Science.

[34]  J. Sanes,et al.  Can molecules explain long-term potentiation? , 1999, Nature Neuroscience.

[35]  W. Abraham,et al.  Induction and Experience-Dependent Consolidation of Stable Long-Term Potentiation Lasting Months in the Hippocampus , 2002, The Journal of Neuroscience.

[36]  T. Abel,et al.  Environmental enrichment modifies the PKA-dependence of hippocampal LTP and improves hippocampus-dependent memory. , 2001, Learning & memory.

[37]  S. Døskeland,et al.  A novel Epac-specific cAMP analogue demonstrates independent regulation of Rap1 and ERK , 2002, Nature Cell Biology.

[38]  R. Morris,et al.  Impaired spatial learning after saturation of long-term potentiation. , 1998, Science.

[39]  K. Jakobs,et al.  Epac- and Ca2+-controlled Activation of Ras and Extracellular Signal-regulated Kinases by Gs-coupled Receptors* , 2004, Journal of Biological Chemistry.

[40]  J. Sweatt,et al.  Mitogen-activated protein kinases in synaptic plasticity and memory , 2004, Current Opinion in Neurobiology.

[41]  S. Mackenzie,et al.  Cyclic nucleotide signalling: a molecular approach to drug discovery for Alzheimer's disease. , 2005, Biochemical Society transactions.

[42]  E. Klann,et al.  NMDA receptor activation results in PKA‐ and ERK‐dependent Mnk1 activation and increased eIF4E phosphorylation in hippocampal area CA1 , 2004, Journal of neurochemistry.

[43]  E. Kandel,et al.  Long-lasting forms of synaptic potentiation in the mammalian hippocampus. , 1996, Learning & memory.

[44]  Isabelle M. Mansuy,et al.  Protein phosphatase 1 is a molecular constraint on learning and memory , 2002, Nature.

[45]  U. Frey,et al.  Influence of actinomycin D, a RNA synthesis inhibitor, on long‐term potentiation in rat hippocampal neurons in vivo and in vitro. , 1996, The Journal of physiology.

[46]  J. Sarvey,et al.  Blockade of long-term potentiation in rat hippocampal CA1 region by inhibitors of protein synthesis , 1984, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[47]  M. Bear,et al.  Chemical induction of mGluR5- and protein synthesis--dependent long-term depression in hippocampal area CA1. , 2001, Journal of neurophysiology.

[48]  Ted Abel,et al.  Temporal spacing of synaptic stimulation critically modulates the dependence of LTP on cyclic AMP‐dependent protein kinase , 2003, Hippocampus.

[49]  A. Wittinghofer,et al.  Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP , 1998, Nature.

[50]  Mark J. Thomas,et al.  Activity-Dependent β-Adrenergic Modulation of Low Frequency Stimulation Induced LTP in the Hippocampal CA1 Region , 1996, Neuron.

[51]  E. Kandel,et al.  Genetic Demonstration of a Role for PKA in the Late Phase of LTP and in Hippocampus-Based Long-Term Memory , 1997, Cell.

[52]  D. Manahan‐Vaughan,et al.  Long-Term Depression: A Cellular Basis for Learning? , 2001, Reviews in the neurosciences.

[53]  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.

[54]  M. Bear,et al.  Extracellular Signal-Regulated Protein Kinase Activation Is Required for Metabotropic Glutamate Receptor-Dependent Long-Term Depression in Hippocampal Area CA1 , 2004, The Journal of Neuroscience.

[55]  R. Huganir,et al.  MAPK cascade signalling and synaptic plasticity , 2004, Nature Reviews Neuroscience.