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The Journal of Neurophysiology Vol. 84 No. 6 December 2000, pp. 2739-2745
Copyright ©2000 by the American Physiological Society
1Department of Physiology and 2Division of Neuroscience, University of Alberta School of Medicine, Edmonton, Alberta T6G 2H7, Canada; and 3Department of Biology and Neuroscience Graduate Group, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Woo, Newton H.,
Steven N. Duffy,
Ted Abel, and
Peter V. Nguyen.
Genetic and Pharmacological Demonstration of Differential
Recruitment of cAMP-Dependent Protein Kinases by Synaptic
Activity. J. Neurophysiol. 84: 2739-2745, 2000. cAMP-dependent protein kinase (PKA) is believed to play a
critical role in the expression of long-lasting forms of hippocampal long-term potentiation (LTP). Can distinct patterns of synaptic activity induce forms of LTP that require different isoforms of PKA? To
address this question, we used transgenic mice that have genetically
reduced hippocampal PKA activity, and a specific pharmacological inhibitor of PKA, Rp-cAMPS. Transgenic mice [R(AB) mice] that express
an inhibitory form of a particular type of regulatory subunit of PKA
(type-I
) showed significantly reduced LTP in area CA1 of hippocampal
slices as compared with slices from wild-type mice. This impairment of
LTP expression was evident when LTP was induced by applying repeated,
temporally spaced stimulation (4 1-s bursts of 100-Hz applied once
every 5 min). In contrast, LTP induced by applying just 60 pulses in a
theta-burst pattern was normal in slices from R(AB) mice as compared
with slices from wild-type mice. We found that Rp-cAMPS blocked the
expression of LTP induced by both spaced tetra-burst and
compressed theta-burst stimulation in hippocampal slices of wild-type
and R(AB) mice, respectively. Since Rp-cAMPS is a PKA inhibitor that is
not selective for any particular isoform of PKA and these R(AB) mice
show reduced hippocampal PKA activity resulting from genetic
manipulation of a single isoform of PKA regulatory subunit, our data
support the idea that distinct patterns of synaptic activity can
produce different forms of LTP that significantly engage different
isoforms of PKA. In particular, theta-burst LTP significantly recruits
isoforms of PKA containing regulatory subunits other than the mutant
RI
subunit, whereas tetra-burst LTP requires PKA isoforms containing the mutant RI
subunit. Thus, altering both the total amount of imposed synaptic activity and the temporal spacing between bursts of
imposed activity may subtly modulate the PKA dependence of hippocampal
LTP by engaging distinct isoforms of PKA. In a broader context, our
findings suggest that synaptic plasticity in the mammalian brain might
be importantly regulated by activity-dependent recruitment of different
isoforms of key signal transduction molecules.
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