Journal article
Genetic and Pharmacological Demonstration of Differential Recruitment of cAMP-Dependent Protein Kinases by Synaptic Activity
Journal of neurophysiology, Vol.84(6), pp.2739-2745
12/01/2000
DOI: 10.1152/jn.2000.84.6.2739
PMID: 11110804
Abstract
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-Iα) 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 RIα subunit, whereas tetra-burst LTP requires PKA isoforms containing the mutant RIα 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.
Details
- Title: Subtitle
- Genetic and Pharmacological Demonstration of Differential Recruitment of cAMP-Dependent Protein Kinases by Synaptic Activity
- Creators
- Newton H Woo - Department of Physiology andSteven N Duffy - Department of Physiology and, Division of Neuroscience, University of Alberta School of Medicine, Edmonton, Alberta T6G 2H7, Canada; andTed Abel - Department of Biology and Neuroscience Graduate Group, University of Pennsylvania, Philadelphia, Pennsylvania 19104Peter V Nguyen - Department of Physiology and, Division of Neuroscience, University of Alberta School of Medicine, Edmonton, Alberta T6G 2H7, Canada; and
- Resource Type
- Journal article
- Publication Details
- Journal of neurophysiology, Vol.84(6), pp.2739-2745
- DOI
- 10.1152/jn.2000.84.6.2739
- PMID
- 11110804
- ISSN
- 0022-3077
- eISSN
- 1522-1598
- Language
- English
- Date published
- 12/01/2000
- Academic Unit
- Molecular Physiology and Biophysics; Psychiatry; Psychological and Brain Sciences; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Biochemistry and Molecular Biology
- Record Identifier
- 9984065824602771
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