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The Journal of Neuroscience, February 15, 2003, 23(4):1142
Postsynaptic Application of a Peptide Inhibitor of cAMP-Dependent
Protein Kinase Blocks Expression of Long-Lasting Synaptic Potentiation
in Hippocampal Neurons
Steven N.
Duffy1, 3 and
Peter V.
Nguyen1, 2, 3
Departments of 1 Physiology and
2 Psychiatry, 3 Centre for
Neuroscience, University of Alberta School of Medicine, Edmonton,
Alberta, T6G 2H7, Canada
Multiple trains of high-frequency synaptic stimulation evoke
long-term potentiation (LTP) of synaptic transmission in hippocampal area CA1, which has been correlated with hippocampal long-term memory
and requires the activation of cAMP-dependent protein kinase (PKA). To
assess whether postsynaptic PKA is necessary for the expression
of LTP, we made prolonged whole-cell voltage-clamp recordings
from CA1 pyramidal neurons in mouse hippocampal slices during
postsynaptic infusion of cell-impermeant modulators of PKA. Repeated
stimulation (four 100 Hz trains at 5 min intervals) of the Schaffer
collateral pathway increased synaptically evoked EPSCs for up to
2 hr. The postsynaptic infusion of either a cell-permeant PKA inhibitor
(Rp-cAMPS) or a cell-impermeant PKA inhibitor (PKI6-22) did not alter post-tetanic peak potentiation, but it caused significant decay of EPSCs to pretetanization amplitudes within 1.5 hr. In contrast, postsynaptic infusion of PKI6-22 did not alter a
more modest, decaying form of LTP evoked by a single 100 Hz train.
Paired-pulse facilitation was unchanged during most of the
duration of LTP, suggesting that postsynaptic mechanisms, including PKA
activation, are involved in the expression of LTP induced by multitrain
stimulation. The postsynaptic infusion of a constitutively active
isoform of the PKA catalytic subunit (C ) into CA1 pyramidal neurons
increased EPSC sizes to elicit long-lasting synaptic facilitation.
Thus, mimicking the activation of PKA in postsynaptic CA1 pyramidal
neurons is sufficient for inducing persistent synaptic facilitation.
Activation of apostsynaptic PKA is necessary for the expression of LTP
in CA1 pyramidal neurons and is sufficient for initiating persistent
synaptic facilitation.
Key words:
synaptic plasticity; hippocampus; LTP; cAMP-dependent protein kinase; catalytic subunit; PKI; whole-cell
recording; postsynaptic; pyramidal neurons; protein kinases
Copyright © 2003 Society for Neuroscience 0270-6474/03/2341142-09$05.00/0
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