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The Journal of Neuroscience, November 1, 2000, 20(21):7880-7887
Long-Term Potentiation Induced by  Frequency Stimulation Is
Regulated by a Protein Phosphatase-1-Operated Gate
George P.
Brown1,
Robert D.
Blitzer2, 3,
John H.
Connor4,
Tony
Wong2,
Shirish
Shenolikar4,
Ravi
Iyengar1, and
Emmanuel M.
Landau1, 2, 3
Departments of 1 Pharmacology and
2 Psychiatry, Mount Sinai School of Medicine, New York, New
York 10029, 3 Psychiatry Service, Bronx Veterans
Administration Medical Center, Bronx, New York 10468, and
4 Department of Pharmacology and Cancer Biology, Duke
University Medical Center, Durham, North Carolina 27712
Long-term potentiation (LTP) can be induced in the Schaffer
collateral CA1 synapse of hippocampus by stimulation in the  frequency range (5-12 Hz), an effect that depends on activation of the
cAMP pathway. We investigated the mechanisms of the cAMP contribution
to this form of LTP in the rat hippocampal slice preparation. pulse
stimulation (TPS; 150 stimuli at 10 Hz) by itself did not induce LTP,
but the addition of either the  -adrenergic agonist isoproterenol or
the cAMP analog 8-bromo-cAMP (8-Br-cAMP) enabled TPS-induced LTP. The
isoproterenol effect was blocked by postsynaptic inhibition of
cAMP-dependent protein kinase. Several lines of evidence indicated that
cAMP enabled LTP by blocking postsynaptic protein phosphatase-1 (PP1).
Activators of the cAMP pathway reduced PP1 activity in the CA1 region
and increased the active form of inhibitor-1, an endogenous inhibitor
of PP1. Postsynaptic injection of activated inhibitor-1 mimicked the
LTP-enabling effect of cAMP pathway stimulation. TPS evoked complex
spiking when isoproterenol was present. However, complex spiking was
not sufficient to enable TPS-induced LTP, which additionally required
the inhibition of postsynaptic PP1. PP1 inhibition seems to promote the
activation of Ca2+/calmodulin-dependent protein
kinase (CaMKII), because (1) a CaMKII inhibitor blocked the
induction of LTP by TPS paired with either isoproterenol or activated
inhibitor-1 and (2) CaMKII in area CA1 was activated by the combination
of TPS and 8-Br-cAMP but not by either stimulus alone. These results
indicate that the cAMP pathway enables TPS-induced LTP by inhibiting
PP1, thereby enhancing Ca2+-independent CaMKII activity.
Key words:
LTP induction; cAMP-dependent protein kinase; inhibitor-1; protein phosphatase-1; Ca2+/calmodulin-dependent protein kinase; gating; complex spikes
Copyright © 2000 Society for Neuroscience 0270-6474/00/20217880-08$05.00/0
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