Hippocampal long-term depression and depotentiation are defective in mice carrying a targeted disruption of the gene encoding the RI beta subunit of cAMP-dependent protein kinase.
The cAMP-dependent protein kinase (PKA) has been shown to play an important role in long-term potentiation (LTP) in the hippocampus, but little is known about the function of PKA in long-term depression (LTD). We have combined pharmacologic and genetic approaches to demonstrate that PKA activity is required for both homosynaptic LTD and depotentiation and that a specific neuronal isoform of type I regulatory subunit (RI beta) is essential. Mice carrying a null mutation in the gene encoding RI beta were established by use of gene targeting in embryonic stem cells. Hippocampal slices from mutant mice show a severe deficit in LTD and depotentiation at the Schaffer collateral-CA1 synapse. This defect is also evident at the lateral perforant path-dentate granule cell synapse in RI beta mutant mice. Despite a compensatory increase in the related RI alpha protein and a lack of detectable changes in total PKA activity, the hippocampal function in these mice is not rescued, suggesting a unique role for RI beta. Since the late phase of CA1 LTP also requires PKA but is normal in RI beta mutant mice, our data further suggest that different forms of synaptic plasticity are likely to employ different combinations of regulatory and catalytic subunits.
Brandon
E P
EP
Graduate Program in Neurobiology, University of Washington School of Medicine, Seattle 98195, USA.
Zhuo
M
M
Huang
Y Y
YY
Qi
M
M
Gerhold
K A
KA
Burton
K A
KA
Kandel
E R
ER
McKnight
G S
GS
Idzerda
R L
RL
D000818:Animals; D054753:Cyclic AMP-Dependent Protein Kinase RIbeta Subunit; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004594:Electrophysiology; D006624:Hippocampus / Q000033:anatomy & histology / Q000201:enzymology / Q000502:physiology*; D006720:Homozygote; D066298:In Vitro Techniques; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction / Q000502:physiology*; D013569:Synapses / Q000502:physiology*
D054753:Cyclic AMP-Dependent Protein Kinase RIbeta Subunit; C517768:Prkar1b protein, mouse; D012333:RNA, Messenger; D017868:Cyclic AMP-Dependent Protein Kinases