Protein Synthesis Is Required for Synaptic Immunity to Depotentiation

De novo protein synthesis and transcription are necessary for the expression of long-lasting synaptic potentiation [long-term potentiation (LTP)] in hippocampal area CA1 and for the consolidation of long-term memory. The stability of LTP and its longevity require macromolecular synthesis at later stages, but a specific role for early protein synthesis has not been identified. Using electrophysiological recording methods in mouse hippocampal slices, we show that multiple trains of high-frequency stimulation provide immediate synaptic immunity to depotentiation. This immunity to depotentiation is dependent on the amount of synaptic stimulation used to induce LTP, it is input specific, and it is prevented by inhibitors of protein synthesis. We propose that local translation mediates input-specific synaptic immunity against depotentiation. We also present evidence suggesting that, in addition to translation, products of transcription can provide cell-wide immunity to depotentiation via heterosynaptic transfer of synaptic immunity between distinct pathways in area CA1. Protein synthesis and transcription may importantly regulate long-term storage of information by conferring synaptic immunity to depotentiation at previously potentiated synapses.

[1]  T. Bliss,et al.  Long‐lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path , 1973, The Journal of physiology.

[2]  G. Lynch,et al.  The effects of repetitive low frequency stimulation on control and "potentiated" synaptic responses in the hippocampus. , 1980, Life sciences.

[3]  W. Levy,et al.  Preferential localization of polyribosomes under the base of dendritic spines in granule cells of the dentate gyrus , 1982, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[4]  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.

[5]  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.

[6]  O. Steward,et al.  Protein-synthetic machinery at postsynaptic sites during synaptogenesis: a quantitative study of the association between polyribosomes and developing synapses , 1986, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[7]  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.

[8]  G. V. Goddard,et al.  Maintenance of long-term potentiation in rat dentate gyrus requires protein synthesis but not messenger RNA synthesis immediately post-tetanization , 1989, Neuroscience.

[9]  M. Waxham,et al.  In situ hybridization histochemistry of Ca2+/calmodulin-dependent protein kinase in developing rat brain , 1990, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[10]  Gary Lynch,et al.  Stable depression of potentiated synaptic responses in the hippocampus with 1–5 Hz stimulation , 1990, Brain Research.

[11]  Hiroshi Kato,et al.  Reversal of long-term potentiation (depotentiation) induced by tetanus stimulation of the input to CA1 neurons of guinea pig hippocampal slices , 1991, Brain Research.

[12]  R. Nicoll,et al.  Mechanisms underlying long-term potentiation of synaptic transmission. , 1991, Annual review of neuroscience.

[13]  O. Steward,et al.  Selective localization of polyribosomes beneath developing synapses: A quantitative analysis of the relationships between polyribosomes and developing synapses in the hippocampus and dentate gyrus , 1991, The Journal of comparative neurology.

[14]  M. Bear,et al.  Homosynaptic long-term depression in area CA1 of hippocampus and effects of N-methyl-D-aspartate receptor blockade. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[15]  O. Steward,et al.  Demonstration of local protein synthesis within dendrites using a new cell culture system that permits the isolation of living axons and dendrites from their cell bodies , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[16]  E. Kandel,et al.  Learning to modulate transmitter release: themes and variations in synaptic plasticity. , 1993, Annual review of neuroscience.

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

[18]  E. Kandel,et al.  Low-frequency stimulation erases LTP through an NMDA receptor-mediated activation of protein phosphatases. , 1994, Learning & memory.

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

[20]  E. Kandel,et al.  Recruitment of long-lasting and protein kinase A-dependent long-term potentiation in the CA1 region of hippocampus requires repeated tetanization. , 1994, Learning & memory.

[21]  U. Frey,et al.  Somatodendritic expression of an immediate early gene is regulated by synaptic activity. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[22]  D. Muller,et al.  Heterosynaptic interactions between UP and LTD in CA1 hippocampal slices , 1995, Neuron.

[23]  Carol A Barnes,et al.  Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites , 1995, Neuron.

[24]  E. Villacres,et al.  Induction of CRE-Mediated Gene Expression by Stimuli That Generate Long-Lasting LTP in Area CA1 of the Hippocampus , 1996, Neuron.

[25]  M. Bear,et al.  Metaplasticity: the plasticity of synaptic plasticity , 1996, Trends in Neurosciences.

[26]  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.

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

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

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

[30]  E. Kandel,et al.  Synapse-Specific, Long-Term Facilitation of Aplysia Sensory to Motor Synapses: A Function for Local Protein Synthesis in Memory Storage , 1997, Cell.

[31]  E. Kandel,et al.  Brief theta-burst stimulation induces a transcription-dependent late phase of LTP requiring cAMP in area CA1 of the mouse hippocampus. , 1997, Learning & memory.

[32]  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.

[33]  Y. Izumi,et al.  Noradrenergic regulation of synaptic plasticity in the hippocampal CA1 region. , 1997, Journal of neurophysiology.

[34]  U. Frey,et al.  Synaptic tagging and long-term potentiation , 1997, Nature.

[35]  E. Kandel,et al.  Genetic and Pharmacological Evidence for a Novel, Intermediate Phase of Long-Term Potentiation Suppressed by Calcineurin , 1998, Cell.

[36]  J. Lisman,et al.  D1/D5 Dopamine Receptors Inhibit Depotentiation at CA1 Synapses via cAMP-Dependent Mechanism , 1998, The Journal of Neuroscience.

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

[38]  U. Frey,et al.  Synaptic tagging: implications for late maintenance of hippocampal long-term potentiation , 1998, Trends in Neurosciences.

[39]  Oswald Steward,et al.  Synaptic Activation Causes the mRNA for the IEG Arc to Localize Selectively near Activated Postsynaptic Sites on Dendrites , 1998, Neuron.

[40]  M. Kennedy,et al.  Tetanic Stimulation Leads to Increased Accumulation of Ca2+/Calmodulin-Dependent Protein Kinase II via Dendritic Protein Synthesis in Hippocampal Neurons , 1999, The Journal of Neuroscience.

[41]  K. Hsu,et al.  A Role for Extracellular Adenosine in Time-Dependent Reversal of Long-Term Potentiation by Low-Frequency Stimulation at Hippocampal CA1 Synapses , 1999, The Journal of Neuroscience.

[42]  M. Bear,et al.  Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression. , 2000, Science.

[43]  S. J. Martin,et al.  Synaptic plasticity and memory: an evaluation of the hypothesis. , 2000, Annual review of neuroscience.

[44]  R. Morris,et al.  Retrograde Amnesia for Spatial Memory Induced by NMDA Receptor-Mediated Long-Term Potentiation , 2001, The Journal of Neuroscience.

[45]  O. Steward,et al.  Protein synthesis at synaptic sites on dendrites. , 2001, Annual review of neuroscience.

[46]  K. Hsu,et al.  Time-Dependent Reversal of Long-Term Potentiation by Low-Frequency Stimulation at the Hippocampal Mossy Fiber–CA3 Synapses , 2001, The Journal of Neuroscience.

[47]  Erin M. Schuman,et al.  Dynamic Visualization of Local Protein Synthesis in Hippocampal Neurons , 2001, Neuron.

[48]  H Terada,et al.  A High-Efficiency Protein Transduction System Demonstrating the Role of PKA in Long-Lasting Long-Term Potentiation , 2001, The Journal of Neuroscience.

[49]  A. Gingras,et al.  A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[50]  K. Hsu,et al.  Progress in Understanding the Factors Regulating Reversibility of Long-term Potentiation , 2001, Reviews in the neurosciences.

[51]  K. Hsu,et al.  Characterization of the Mechanism Underlying the Reversal of Long Term Potentiation by Low Frequency Stimulation at Hippocampal CA1 Synapses* 210 , 2001, The Journal of Biological Chemistry.

[52]  P. Nguyen,et al.  "Silent" metaplasticity of the late phase of long-term potentiation requires protein phosphatases. , 2002, Learning & memory.

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

[54]  Eric R. Kandel,et al.  Expression of Constitutively Active CREB Protein Facilitates the Late Phase of Long-Term Potentiation by Enhancing Synaptic Capture , 2002, Cell.

[55]  S. Redman,et al.  Different calcium sources are narrowly tuned to the induction of different forms of LTP. , 2002, Journal of neurophysiology.

[56]  M. Mayford,et al.  Disruption of Dendritic Translation of CaMKIIα Impairs Stabilization of Synaptic Plasticity and Memory Consolidation , 2002, Neuron.

[57]  T. Bliss,et al.  Brain-Derived Neurotrophic Factor Induces Long-Term Potentiation in Intact Adult Hippocampus: Requirement for ERK Activation Coupled to CREB and Upregulation of Arc Synthesis , 2002, The Journal of Neuroscience.

[58]  T. Abel,et al.  Protein synthesis is required for the enhancement of long-term potentiation and long-term memory by spaced training. , 2002, Journal of neurophysiology.

[59]  G. Collingridge,et al.  An investigation of depotentiation of long-term potentiation in the CA1 region of the hippocampus , 1994, Experimental Brain Research.