Protein Phosphatase-Mediated Regulation of Protein Kinase C during Long-Term Depression in the Adult Hippocampus In Vivo

• Published in: The Journal of neuroscience Vol. 20; no. 19; pp. 7199 - 7207
• Main Authors: Thiels, Edda, Kanterewicz, Beatriz I, Knapp, Lauren T, Barrionuevo, German, Klann, Eric
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 01.10.2000; Society for Neuroscience
• Subjects: 2-Amino-5-phosphonovalerate - pharmacology; Action Potentials - drug effects; Animals; Catalytic Domain - drug effects; Enzyme Inhibitors - pharmacology; Hippocampus - enzymology; Hippocampus - physiology; Isoenzymes - metabolism; Learning - physiology; Memory - physiology; Neural Inhibition - physiology; Okadaic Acid - pharmacology; Phosphoprotein Phosphatases - antagonists & inhibitors; Phosphoprotein Phosphatases - metabolism; Phosphorus Radioisotopes; Phosphorylation - drug effects; Protein Kinase C - metabolism; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Synaptic Transmission - physiology; Time
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.20-19-07199.2000

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 PKCalpha, beta, gamma, or zeta. Western blot analysis with phosphospecific antibodies revealed that phosphorylation of Ser-657 on the catalytic domain of PKCalpha (Ser-660 on PKCbetaII) 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.