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.
Krucker
Thomas
T
Departments of Neuropharmacology and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Siggins
George R
GR
McNamara
Robert K
RK
Lindsley
Kristen A
KA
Dao
Alan
A
Allison
David W
DW
De Lecea
Luis
L
Lovenberg
Timothy W
TW
Sutcliffe
J Gregor
JG
Gerendasy
Dan D
DD
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002147:Calmodulin / Q000502:physiology*; D002148:Calmodulin-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D002478:Cells, Cultured; D019706:Excitatory Postsynaptic Potentials; D018390:Gene Targeting; D006624:Hippocampus / Q000502:physiology*; D007700:Kinetics; D017774:Long-Term Potentiation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008959:Models, Neurological; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology*; D051579:Neurogranin; D009473:Neuronal Plasticity; D010641:Phenotype; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists; D009435:Synaptic Transmission
D002147:Calmodulin; D002148:Calmodulin-Binding Proteins; D009419:Nerve Tissue Proteins; C496650:Nrgn protein, mouse; D018094:Receptors, Metabotropic Glutamate; D051579:Neurogranin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases