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Volume 16, Number 17,
Issue of September 1, 1996
pp. 5324-5333
Copyright ©1996 Society for Neuroscience
Bidirectional Regulation of Protein Kinase M in the
Maintenance of Long-Term Potentiation and Long-Term Depression
Received Jan. 24, 1996; revised May 30, 1996; accepted June 6, 1996.
Sabina Hrabetova and
Todd Charlton Sacktor
Laboratory of Molecular Neuroscience, Departments of Pharmacology
and Neurology, State University of New York at Brooklyn, Brooklyn, New
York 11203
Long-term potentiation (LTP) and long-term depression (LTD) are
persistent modifications of synaptic efficacy that may contribute to
information storage in the CA1 region of the hippocampus. Persistently
enhanced phosphorylation has been implicated in the maintenance phase
of LTP. This hypothesis is supported by our previous observation that
protein kinase M (PKM), the constitutively active catalytic
fragment of a single protein kinase C isoform (PKC), increases in
LTP maintenance. In contrast, dephosphorylation may be important in LTD
maintenance, because phosphatase inhibitors reverse established LTD, in
addition to blocking its induction. Because phosphorylation is
determined by a balance of phosphatases and kinases, both increases in
phosphatase activity and decreases in kinase activity could contribute
to LTD. We now report that the reduction of protein kinase activity by
H7, as well as selective inhibition of PKC by chelerythrine, mimics and
occludes the maintenance phase of homosynaptic LTD in rat hippocampal
slices. Conversely, saturated LTD occludes the synaptic depression
caused by chelerythrine. Biochemical analysis demonstrates a decrease
of PKM, as well as PKCs  and  , in LTD maintenance and a
concomitant loss of constitutive PKC activity. LTD and the
downregulation of PKM are prevented by NMDA receptor antagonists and
Ca2+-dependent protease inhibitors. Both LTD and the
downregulation of PKM are reversible by high-frequency afferent
stimulation. Our findings indicate that the molecular mechanisms of LTP
and LTD maintenance are inversely related through the bidirectional
regulation of PKC.
Key words:
long-term potentiation;
long-term depression;
phosphorylation;
dephosphorylation;
protein kinase C zeta isozyme;
PKM;
learning and memory
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