Long-Term Potentiation Induced by theta Frequency Stimulation Is Regulated by a Protein Phosphatase-1-Operated Gate

Long-term potentiation (LTP) can be induced in the Schaffer collateral-->CA1 synapse of hippocampus by stimulation in the theta 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 r...

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Bibliographic Details
Published in:The Journal of neuroscience 2000-11, Vol.20 (21), p.7880-7887
Main Authors: Brown, George P, Blitzer, Robert D, Connor, John H, Wong, Tony, Shenolikar, Shirish, Iyengar, Ravi, Landau, Emmanuel M
Format: Article
Language:English
Subjects:
8-Bromo Cyclic Adenosine Monophosphate - pharmacology
Action Potentials - drug effects
Adrenergic beta-Agonists - pharmacology
Animals
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Calcium-Calmodulin-Dependent Protein Kinases - metabolism
Cyclic AMP - metabolism
Cyclic AMP - pharmacology
Electric Stimulation
Excitatory Amino Acid Antagonists - pharmacology
Excitatory Postsynaptic Potentials - drug effects
Hippocampus - cytology
Hippocampus - drug effects
Hippocampus - metabolism
In Vitro Techniques
Ion Channel Gating - physiology
Long-Term Potentiation - drug effects
Long-Term Potentiation - physiology
Male
Neuronal Plasticity - physiology
Phosphoprotein Phosphatases - antagonists & inhibitors
Phosphoprotein Phosphatases - metabolism
Protein Phosphatase 1
Proteins - genetics
Proteins - pharmacology
Rats
Rats, Sprague-Dawley
Receptors, AMPA - antagonists & inhibitors
Signal Transduction - drug effects
Signal Transduction - physiology
Synaptic Transmission - drug effects
Theta Rhythm
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Summary:Long-term potentiation (LTP) can be induced in the Schaffer collateral-->CA1 synapse of hippocampus by stimulation in the theta 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. theta pulse stimulation (TPS; 150 stimuli at 10 Hz) by itself did not induce LTP, but the addition of either the beta-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 Ca(2+)/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 Ca(2+)-independent CaMKII activity.
ISSN:0270-6474
1529-2401
DOI:10.1523/jneurosci.20-21-07880.2000