Restricted and Regulated Overexpression Reveals Calcineurin as a Key Component in the Transition from Short-Term to Long-Term Memory

To investigate the roles phosphatases play in hippocampal-dependent memory, we studied transgenic mice overexpressing a truncated form of calcineurin. These mice have normal short-term memory but defective long-term memory evident on both a spatial task and on a visual recognition task, providing genetic evidence for the role of the rodent hippocampus in spatial and nonspatial memory. The defect in long-term memory could be fully rescued by increasing the number of training trials, suggesting that the mice have the capacity for long-term memory. We next analyzed mice overexpressing calcineurin in a regulated manner and found the memory defect is reversible and not due to a developmental abnormality. Our behavioral results suggest that calcineurin has a role in the transition from short- to long-term memory, which correlates with a novel intermediate phase of LTP.

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

[2]  Weiqin Zhao,et al.  The impairment of long-term memory formation by the phosphatase inhibitor okadaic acid , 1995, Brain Research Bulletin.

[3]  R. Knight.  Contribution of human hippocampal region to novelty detection , 1996, Nature.

[4]  T. Préat,et al.  Genetic dissection of consolidated memory in Drosophila , 1994, Cell.

[5]  K. A. Lee,et al.  Transcriptional regulation by CREB and its relatives. , 1993, Biochimica et biophysica acta.

[6]  D. Mumby,et al.  Memory deficits following lesions of hippocampus or amygdala in rat: Assessment by an object-memory test battery , 1995, Psychobiology.

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

[8]  M. Gossen,et al.  Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[9]  L R Squire,et al.  Impaired recognition memory in patients with lesions limited to the hippocampal formation. , 1997, Behavioral neuroscience.

[10]  R. Iyengar,et al.  Postsynaptic CAMP pathway gates early LTP in hippocampal CA1 region , 1995, Neuron.

[11]  M. Montminy,et al.  The CREB family of transcription activators , 1992, Current Biology.

[12]  Wayne A. Wickelgren,et al.  The long and the short of memory. , 1973 .

[13]  D. Spalding.  The Principles of Psychology , 1873, Nature.

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

[15]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[16]  R. Jaenisch,et al.  A generic intron increases gene expression in transgenic mice , 1991, Molecular and cellular biology.

[17]  E. A. O'neill,et al.  FK-506- and CsA-sensitive activation of the interleukin-2 promoter by calcineurin , 1992, Nature.

[18]  T. Myhrer.  The role of medial and lateral hippocampal perforant path lesions and object distinctiveness in rats' reaction to novelty , 1988, Physiology & Behavior.

[19]  R. Hinde,et al.  Short-Term Changes in Neural Activity and Behaviour , 1972 .

[20]  B. Frieder,et al.  Memory consolidation: Further evidence for the four-phase model from the time-courses of diethyldithiocarbamate and ethacrinic acid amnesias , 1982, Physiology & Behavior.

[21]  F. Gage,et al.  Enhanced detection of nucleus basalis magnocellularis lesion-induced spatial learning deficit in rats by modification of training regimen , 1989, Behavioural Brain Research.

[22]  E. Kandel,et al.  Control of Memory Formation Through Regulated Expression of a CaMKII Transgene , 1996, Science.

[23]  M. Mishkin,et al.  Dissociation of the effects of inferior temporal and limbic lesions on object discrimination learning with 24-h intertrial intervals , 1988, Behavioural Brain Research.

[24]  C. Barnes.  Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat. , 1979, Journal of comparative and physiological psychology.

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

[26]  F. Craik,et al.  Levels of Pro-cessing: A Framework for Memory Research , 1975 .

[27]  A. Cherkin.  Kinetics of memory consolidation: role of amnesic treatment parameters. , 1969, Proceedings of the National Academy of Sciences of the United States of America.

[28]  L. Squire,et al.  Medial temporal lesions in monkeys impair memory on a variety of tasks sensitive to human amnesia. , 1985, Behavioral neuroscience.

[29]  L. Voronin,et al.  Long-term potentiation in the hippocampus , 1983, Neuroscience.

[30]  P. Cohen,et al.  Isolation and characterization of bovine brain calcineurin: a calmodulin-stimulated protein phosphatase. , 1983, Methods in enzymology.

[31]  T. Myhrer.  Exploratory behavior and reaction to novelty in rats with hippocampal perforant path systems disrupted. , 1988, Behavioral neuroscience.

[32]  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.

[33]  F. Craik,et al.  Novelty and familiarity activations in PET studies of memory encoding and retrieval. , 1996, Cerebral cortex.

[34]  K. Ng,et al.  Psychobiology of memory: Towards a model of memory formation , 1977 .

[35]  Edward L. Bennett,et al.  Short-term, intermediate-term, and long-term memories , 1993, Behavioural Brain Research.

[36]  D. Amaral,et al.  Memory and the Hippocampus , 1989 .

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

[38]  L. Squire.  Memory and Brain , 1987 .

[39]  H. Eichenbaum.  The LTP–memory connection , 1995, Nature.

[40]  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.

[41]  L. Squire.  Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. , 1992, Psychological review.

[42]  J. Delacour,et al.  A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data , 1988, Behavioural Brain Research.

[43]  M. Mishkin.  Memory in monkeys severely impaired by combined but not by separate removal of amygdala and hippocampus , 1978, Nature.

[44]  P Alvarez,et al.  The animal model of human amnesia: long-term memory impaired and short-term memory intact. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[45]  E. Kandel,et al.  Impairment of spatial but not contextual memory in CaMKII mutant mice with a selective loss of hippocampal ltp in the range of the θ frequency , 1995, Cell.

[46]  W. Scoville,et al.  LOSS OF RECENT MEMORY AFTER BILATERAL HIPPOCAMPAL LESIONS , 1957, Journal of neurology, neurosurgery, and psychiatry.

[47]  L. Squire.  "Memory and the hippocampus: A synthesis from findings with rats, monkeys, and humans": Correction. , 1992 .

[48]  J. Aggleton,et al.  One-Trial Object Recognition by Rats , 1985 .

[49]  K. Ng,et al.  Cyclosporin A, an inhibitor of calcineurin, impairs memory formation in day-old chicks , 1996, Brain Research.

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