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The Journal of Neuroscience, October 1, 2000, 20(19):7199-7207
Protein Phosphatase-Mediated Regulation of Protein Kinase C
during Long-Term Depression in the Adult Hippocampus In
Vivo
Edda
Thiels,
Beatriz I.
Kanterewicz,
Lauren T.
Knapp,
German
Barrionuevo, and
Eric
Klann
Department of Neuroscience and Center for the Neural Basis of
Cognition, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
The neural substrates of learning and memory are thought to involve
use-dependent long-term changes in synaptic function, including
long-term depression (LTD) of synaptic strength. One biochemical event
hypothesized to contribute to the maintenance and expression of LTD is
decreased protein phosphorylation, caused by a decrease in protein
kinase activity and/or an increase in protein phosphatase activity. We
tested whether the activity of protein kinase C (PKC) decreases after
the induction of LTD in area CA1 of the adult hippocampus in
vivo, and then investigated the mechanism responsible for the
LTD-associated alteration in PKC activity. We found that LTD was
associated with a significant decrease in both autonomous and
cofactor-dependent PKC activity. The decrease in PKC activity was
prevented by NMDA receptor blockade and was not accompanied by a
decrease in the level of either PKC ,  ,  , or  . Western blot
analysis with phosphospecific antibodies revealed that phosphorylation
of Ser-657 on the catalytic domain of PKC (Ser-660 on PKCII) was
decreased significantly after the induction of LTD, and that this
dephosphorylation was prevented by the protein phosphatase inhibitor
okadaic acid. The decrease in autonomous and cofactor-dependent PKC
activity likewise was prevented by okadaic acid. These findings suggest
that LTD in the adult hippocampus in vivo involves a
decrease in PKC activity that is mediated, at least in part, by
dephosphorylation of the catalytic domain of PKC by protein
phosphatases activated after LTD-inducing stimulation. Our findings are
consistent with the idea that protein dephosphorylation contributes to
the expression of LTD.
Key words:
long-term depression; protein kinase C; protein
phosphatase; dephosphorylation; area CA1; learning and memory
Copyright © 2000 Society for Neuroscience 0270-6474/00/20197199-09$05.00/0
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