Genetic and pharmacological evidence for a novel, intermediate phase of long-term potentiation suppressed by calcineurin

Cell. 1998 Jan 9;92(1):25-37. doi: 10.1016/s0092-8674(00)80896-x.

Abstract

To investigate the role of phosphatases in synaptic plasticity using genetic approaches, we generated transgenic mice that overexpress a truncated form of calcineurin under the control of the CaMKIIalpha promoter. Mice expressing this transgene show increased calcium-dependent phosphatase activity in the hippocampus. Physiological studies of these mice and parallel pharmacological experiments in wild-type mice reveal a novel, intermediate phase of LTP (I-LTP) in the CA1 region of the hippocampus. This intermediate phase differs from E-LTP by requiring multiple trains for induction and in being dependent on PKA. It differs from L-LTP in not requiring new protein synthesis. These data suggest that calcineurin acts as an inhibitory constraint on I-LTP that is relieved by PKA. This inhibitory constraint acts as a gate to regulate the synaptic induction of L-LTP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / physiology
  • Animals
  • Calcineurin / genetics
  • Calcineurin / physiology*
  • Cyclic AMP-Dependent Protein Kinases / pharmacology
  • Cyclic AMP-Dependent Protein Kinases / physiology
  • Electric Stimulation
  • Enzyme Inhibitors / pharmacology
  • Excitatory Postsynaptic Potentials / physiology
  • Female
  • Gene Expression / genetics
  • Gene Expression / physiology
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / physiology
  • Genetic Engineering
  • Hippocampus / chemistry
  • Hippocampus / metabolism
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / genetics
  • Long-Term Potentiation / physiology*
  • Male
  • Mice
  • Mice, Inbred CBA
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Phosphoprotein Phosphatases / antagonists & inhibitors
  • Phosphoric Monoester Hydrolases / physiology
  • Protein Biosynthesis
  • Proteins / drug effects
  • Pyramidal Cells / physiology
  • Recombinant Proteins / genetics
  • Stimulation, Chemical
  • Synapses / physiology
  • Synaptic Transmission / genetics
  • Synaptic Transmission / physiology
  • Transgenes / genetics
  • Transgenes / physiology

Substances

  • Enzyme Inhibitors
  • Proteins
  • Recombinant Proteins
  • Cyclic AMP-Dependent Protein Kinases
  • Calcineurin
  • Phosphoprotein Phosphatases
  • Phosphoric Monoester Hydrolases