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Targeted disruption of rc3 reveals a calmodulin-based mechanism for regulating metaplasticity in the hippocampus

Academic Article
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Overview

authors

  • Krucker, T.
  • Siggins, George
  • McNamara, R. K.
  • Lindsley, K. A.
  • Dao, A.
  • Allison, D. W.
  • de Lecea, L.
  • Lovenberg, T. W.
  • Sutcliffe, J. Gregor
  • Gerendasy, D. D.

publication date

  • July 2002

journal

  • Journal of Neuroscience  Journal

abstract

  • 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.

subject areas

  • 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
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Research

keywords

  • CaMKII
  • LTD
  • LTP
  • PKC gamma
  • calcium
  • dendrite
  • dendritic spine
  • depotentiation
  • frequency response
  • mGluR
  • metaplasticity
  • molecular switch
  • neurogranin
  • neuroplasticity
  • postsynaptic
  • priming
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Identity

International Standard Serial Number (ISSN)

  • 0270-6474

PubMed ID

  • 12097504
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Additional Document Info

start page

  • 5525

end page

  • 5535

volume

  • 22

issue

  • 13

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