Postsynaptic application of a peptide inhibitor of cAMP-dependent protein kinase blocks expression of long-lasting synaptic potentiation in hippocampal neurons.
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 (PKI(6-22)) 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 PKI(6-22) 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 (Calpha) 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.
Duffy
Steven N
SN
Department of Physiology, University of Alberta School of Medicine, Edmonton, Alberta, T6G 2H7, Canada.
Nguyen
Peter V
PV
D000818:Animals; D002352:Carrier Proteins / Q000494:pharmacology; D002478:Cells, Cultured; D023902:Chromosome Pairing / Q000187:drug effects / Q000502:physiology; D005576:Colforsin / Q000037:antagonists & inhibitors; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D004553:Electric Conductivity; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials; D018698:Glutamic Acid / Q000502:physiology; D006624:Hippocampus / Q000166:cytology*; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D017774:Long-Term Potentiation; D051379:Mice; D008810:Mice, Inbred C57BL; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000494:pharmacology; D017966:Pyramidal Cells / Q000201:enzymology / Q000502:physiology*; D009435:Synaptic Transmission; D013873:Thionucleotides / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D010446:Peptide Fragments; D013873:Thionucleotides; C094636:protein kinase inhibitor (6-22); D005576:Colforsin; C016957:adenosine-3',5'-cyclic phosphorothioate; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases