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Inducible and reversible enhancement of learning, memory, and long-term potentiation by genetic inhibition of calcineurin.

The threshold for hippocampal-dependent synaptic plasticity and memory storage is thought to be determined by the balance between protein phosphorylation and dephosphorylation mediated by the kinase PKA and the phosphatase calcineurin. To establish whether endogenous calcineurin acts as an inhibitory constraint in this balance, we examined the effect of genetically inhibiting calcineurin on plasticity and memory. Using the doxycycline-dependent rtTA system to express a calcineurin inhibitor reversibly in the mouse brain, we find that the transient reduction of calcineurin activity facilitates LTP in vitro and in vivo. This facilitation is PKA dependent and persists over several days in vivo. It is accompanied by enhanced learning and strengthened short- and long-term memory in several hippocampal-dependent spatial and nonspatial tasks. The LTP and memory improvements are reversed fully by suppression of transgene expression. These results demonstrate that endogenous calcineurin constrains LTP and memory.

Pubmed ID: 11257222

Authors

  • Malleret G
  • Haditsch U
  • Genoux D
  • Jones MW
  • Bliss TV
  • Vanhoose AM
  • Weitlauf C
  • Kandel ER
  • Winder DG
  • Mansuy IM

Journal

Cell

Publication Data

March 9, 2001

Associated Grants

None

Mesh Terms

  • Animals
  • Anti-Bacterial Agents
  • Calcineurin
  • Calcineurin Inhibitors
  • Conditioning (Psychology)
  • Dentate Gyrus
  • Doxycycline
  • Electric Stimulation
  • Form Perception
  • Gene Expression Regulation
  • In Vitro Techniques
  • Long-Term Potentiation
  • Memory, Short-Term
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neuronal Plasticity
  • Signal Transduction
  • Transgenes