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

• Published in: The Journal of neuroscience 2002-07, Vol.22 (13), p.5525-5535
• Main Authors: Krucker, Thomas, Siggins, George R, McNamara, Robert K, Lindsley, Kristen A, Dao, Alan, Allison, David W, de Lecea, Luis, Lovenberg, Timothy W, Sutcliffe, J. Gregor, Gerendasy, Dan D
• Format: Article
• Language: English
• Subjects: Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Calmodulin - physiology; Calmodulin-Binding Proteins - genetics; Calmodulin-Binding Proteins - physiology; Cells, Cultured; Excitatory Postsynaptic Potentials; Gene Targeting; Hippocampus - physiology; Kinetics; Long-Term Potentiation; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Neurological; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - physiology; Neurogranin; Neuronal Plasticity; Phenotype; Receptors, Metabotropic Glutamate - agonists; Synaptic Transmission
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.22-13-05525.2002

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.