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The Journal of Neuroscience, July 1, 2002, 22(13):5525-5535

Targeted Disruption of RC3 Reveals a Calmodulin-Based Mechanism for Regulating Metaplasticity in the Hippocampus

Thomas Krucker¹, George R. Siggins¹, Robert K. McNamara³, Kristen A. Lindsley², Alan Dao², David W. Allison¹, Luis de Lecea², Timothy W. Lovenberg², J. Gregor Sutcliffe², and Dan D. Gerendasy²

Departments of ¹ Neuropharmacology and ² Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, and ³ Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104

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.

Key words: neurogranin; PKC; CaMKII; metaplasticity; mGluR; neuroplasticity; LTP; LTD; depotentiation; priming; molecular switch; postsynaptic; frequency response; calcium; dendrite; dendritic spine

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22135525-11$05.00/0

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