The ubiquitin–proteasome cascade is required for mammalian long‐term memory formation

It has been recently demonstrated that ubiquitin–proteasome‐mediated proteolysis is required for long‐term synaptic facilitation in Aplysia. Here we show that the hippocampal blockade of this proteolytic pathway is also required for the formation of long‐term memory in the rat. Bilateral infusion of lactacystin, a specific proteasome inhibitor, to the CA1 region caused full retrograde amnesia for a one‐trial inhibitory avoidance learning when given 1, 4 or 7h, but not 10 h, after training. Proteasome inhibitor I produced similar effects. In addition, inhibitory avoidance training resulted in an increased ubiquitination and 26S proteasome proteolytic activity and a decrease in the levels of IkappaB, a substrate of the ubiquitin–proteasome cascade, in hippocampus 4 h after training. Together, these findings indicate that the ubiquitin–proteasome cascade is crucial for the establishment of LTM in the behaving animal.

[1]  I. Khalilov,et al.  Early sequential formation of functional GABAA and glutamatergic synapses on CA1 interneurons of the rat foetal hippocampus , 2002, The European journal of neuroscience.

[2]  S. Ōmura,et al.  Activation of Atypical Protein Kinase C ζ by Caspase Processing and Degradation by the Ubiquitin-Proteasome System* , 2000, The Journal of Biological Chemistry.

[3]  G. Elston,et al.  Pyramidal Cells, Patches, and Cortical Columns: a Comparative Study of Infragranular Neurons in TEO, TE, and the Superior Temporal Polysensory Area of the Macaque Monkey , 2000, The Journal of Neuroscience.

[4]  I. Izquierdo,et al.  Phosphorylated cAMP Response Element-Binding Protein as a Molecular Marker of Memory Processing in Rat Hippocampus: Effect of Novelty , 2000, The Journal of Neuroscience.

[5]  J. D. McGaugh,et al.  Behavioural pharmacology and its contribution to the molecular basis of memory consolidation. , 2000, Behavioural pharmacology.

[6]  J. Pasquini,et al.  Defective ubiquitination of cerebral proteins in Alzheimer's disease , 2000, Journal of neuroscience research.

[7]  U. Müller.  Prolonged Activation of cAMP-Dependent Protein Kinase during Conditioning Induces Long-Term Memory in Honeybees , 2000, Neuron.

[8]  V. Berezin,et al.  A Synthetic Peptide Ligand of Neural Cell Adhesion Molecule (NCAM) IgI Domain Prevents NCAM Internalization and Disrupts Passive Avoidance Learning , 2000, Journal of neurochemistry.

[9]  I. Izquierdo,et al.  Learning-associated activation of nuclear MAPK, CREB and Elk-1, along with Fos production, in the rat hippocampus after a one-trial avoidance learning: abolition by NMDA receptor blockade. , 2000, Brain research. Molecular brain research.

[10]  P. Calabresi,et al.  Tissue plasminogen activator controls multiple forms of synaptic plasticity and memory , 2000, The European journal of neuroscience.

[11]  A. Romano,et al.  Participation of Rel/NF-κB transcription factors in long-term memory in the crab Chasmagnathus , 2000, Brain Research.

[12]  I. Izquierdo,et al.  Involvement of hippocampal PKCβI isoform in the early phase of memory formation of an inhibitory avoidance learning , 2000, Brain Research.

[13]  J. D. McGaugh.  Memory--a century of consolidation. , 2000, Science.

[14]  M. Bear,et al.  A molecular correlate of memory and amnesia in the hippocampus , 1999, Nature Neuroscience.

[15]  Samuel Schacher,et al.  Mechanisms for Generating the Autonomous cAMP-Dependent Protein Kinase Required for Long-Term Facilitation in Aplysia , 1999, Neuron.

[16]  Uli Müller,et al.  Serotonin Induces Temporally and Mechanistically Distinct Phases of Persistent PKA Activity in Aplysia Sensory Neurons , 1998, Neuron.

[17]  Gregor Eichele,et al.  Mutation of the Angelman Ubiquitin Ligase in Mice Causes Increased Cytoplasmic p53 and Deficits of Contextual Learning and Long-Term Potentiation , 1998, Neuron.

[18]  I. Izquierdo,et al.  Mechanisms for memory types differ , 1998, Nature.

[19]  U. Müller,et al.  Induction of a Specific Olfactory Memory Leads to a Long-Lasting Activation of Protein Kinase C in the Antennal Lobe of the Honeybee , 1998, The Journal of Neuroscience.

[20]  E. Kandel,et al.  Cognitive Neuroscience and the Study of Memory , 1998, Neuron.

[21]  I. Izquierdo,et al.  Memory Formation: The Sequence of Biochemical Events in the Hippocampus and Its Connection to Activity in Other Brain Structures , 1997, Neurobiology of Learning and Memory.

[22]  I Izquierdo,et al.  Involvement of hippocampal cAMP/cAMP-dependent protein kinase signaling pathways in a late memory consolidation phase of aversively motivated learning in rats. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[23]  C. Kaltschmidt,et al.  NF-kB: a crucial transcription factor for glial and neuronal cell function , 1997, Trends in Neurosciences.

[24]  James H. Schwartz,et al.  Ubiquitin C-Terminal Hydrolase Is an Immediate-Early Gene Essential for Long-Term Facilitation in Aplysia , 1997, Cell.

[25]  Benedetto Sacchetti,et al.  Role of dorsal hippocampus in acquisition, consolidation and retrieval of rat's passive avoidance response: a tetrodotoxin functional inactivation study , 1996, Brain Research.

[26]  A. Routtenberg,et al.  Gene expression of the transcription factor NF-kappa B in hippocampus: regulation by synaptic activity. , 1996, Brain research. Molecular brain research.

[27]  A. Ciechanover,et al.  Persistent activation of cAMP-dependent protein kinase by regulated proteolysis suggests a neuron-specific function of the ubiquitin system in Aplysia , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[28]  R F Standaert,et al.  Inhibition of proteasome activities and subunit-specific amino-terminal threonine modification by lactacystin , 1995, Science.

[29]  I. Izquierdo,et al.  Post-training intrahippocampal infusion of protein kinase C inhibitors causes amnesia in rats. , 1994, Behavioral and neural biology.

[30]  R. Jaffard,et al.  Protein kinase C activity in the hippocampus following spatial learning tasks in mice , 1994, Hippocampus.

[31]  S. Tonegawa,et al.  PKCγ mutant mice exhibit mild deficits in spatial and contextual learning , 1993, Cell.

[32]  J. H. Schwartz,et al.  Regulatory subunits of cAMP-dependent protein kinases are degraded after conjugation to ubiquitin: a molecular mechanism underlying long-term synaptic plasticity. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[33]  A. Routtenberg,et al.  Learning selectively increases protein kinase C substrate phosphorylation in specific regions of the chick brain. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[34]  Eric R. Kandel,et al.  Tissue-plasminogen activator is induced as an immediate–early gene during seizure, kindling and long-term potentiation , 1993, Nature.

[35]  C. Regan,et al.  Intraventricular Infusions of Anti‐Neural Cell Adhesion Molecules in a Discrete Posttraining Period Impair Consolidation of a Passive Avoidance Response in the Rat , 1992, Journal of neurochemistry.

[36]  D L Alkon,et al.  Imaging of memory-specific changes in the distribution of protein kinase C in the hippocampus. , 1989, Science.

[37]  L. Squire,et al.  Protein synthesis and memory: a review. , 1984, Psychological bulletin.

[38]  G. Lynch,et al.  The biochemistry of memory: a new and specific hypothesis. , 1984, Science.

[39]  L. Swanson.  The Rat Brain in Stereotaxic Coordinates, George Paxinos, Charles Watson (Eds.). Academic Press, San Diego, CA (1982), vii + 153, $35.00, ISBN: 0 125 47620 5 , 1984 .

[40]  Robert Thompson,et al.  Localization of a “passive avoidance memory system”in the white rat , 1978 .

[41]  G. Winocur,et al.  Effects of additional cues on passive avoidance learning and extinction in rats with hippocampal lesions , 1976, Physiology & Behavior.

[42]  R. Bernabeu,et al.  Involvement of hippocampal D1/D5 receptor-cAMP signaling pathways in a late memory consolidation phase of an aversively-motivated task in rats , 1997 .

[43]  A. Baldwin,et al.  THE NF-κB AND IκB PROTEINS: New Discoveries and Insights , 1996 .

[44]  A. Baldwin,et al.  The NF-kappa B and I kappa B proteins: new discoveries and insights. , 1996, Annual review of immunology.