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Targeted disruption of RC3 reveals a calmodulin-based mechanism for regulating metaplasticity in the hippocampus.

We used homologous recombination in the mouse to knock-out RC3, a postsynaptic, calmodulin-binding PKC substrate. Mutant brains exhibited lower immunoreactivity to phospho-Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) but had the same synaptic density as wild type and did not exhibit a gross neuroanatomical phenotype. Basal excitatory synaptic transmission in CA1 was depressed, long-term potentiation (LTP) was enhanced, and the depressant effects of the metabotropic glutamate receptor (mGluR) agonist (RS)-3,5-dihydroxyphenylglycine was occluded compared with littermate controls. The frequency-response curve was displaced to the left, and long-term depression (LTD) could not be induced unless low-frequency stimuli were preceded by high-frequency tetani. Depotentiation was much more robust in the mutant, and only one stimulus was required to saturate LTD in primed mutant hippocampi, whereas multiple low-frequency stimuli were required in wild-type slices. Thus, ablation of RC3 appears to render the postsynaptic neuron hypersensitive to Ca(2+), decreasing its LTD and LTP thresholds and accentuating the effects of priming stimuli. We propose an mGluR-dependent CaM-based sliding threshold mechanism for metaplasticity that is governed by the phosphorylation states of RC3 and CaMKII.

Pubmed ID: 12097504

Authors

  • Krucker T
  • Siggins GR
  • McNamara RK
  • Lindsley KA
  • Dao A
  • Allison DW
  • De Lecea L
  • Lovenberg TW
  • Sutcliffe JG
  • Gerendasy DD

Journal

The Journal of neuroscience : the official journal of the Society for Neuroscience

Publication Data

July 1, 2002

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM32355
  • Agency: NIMH NIH HHS, Id: MH44346
  • Agency: NIMH NIH HHS, Id: MH47680
  • Agency: NINDS NIH HHS, Id: NS35831

Mesh Terms

  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Calmodulin
  • Calmodulin-Binding Proteins
  • Cells, Cultured
  • Excitatory Postsynaptic Potentials
  • Gene Targeting
  • Hippocampus
  • Kinetics
  • Long-Term Potentiation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Neurological
  • Nerve Tissue Proteins
  • Neurogranin
  • Neuronal Plasticity
  • Phenotype
  • Receptors, Metabotropic Glutamate
  • Synaptic Transmission