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

Thomas Krucker, George R. Siggins, Robert K. McNamara, Kristen A. Lindsley, Alan Dao, David W. Allison, Luis De Lecea, Timothy W. Lovenberg, J. Gregor Sutcliffe, Dan D. Gerendasy

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

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-Ca2+/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 Ca2+, 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.

Original languageEnglish (US)
Pages (from-to)5525-5535
Number of pages11
JournalJournal of Neuroscience
Volume22
Issue number13
DOIs
StatePublished - Jul 1 2002

Keywords

  • Calcium
  • CaMKII
  • Dendrite
  • Dendritic spine
  • Depotentiation
  • Frequency response
  • LTD
  • LTP
  • Metaplasticity
  • mGluR
  • Molecular switch
  • Neurogranin
  • Neuroplasticity
  • PKCγ
  • Postsynaptic
  • Priming

ASJC Scopus subject areas

  • Neuroscience(all)

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