Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory.
To explore the role of protein kinase A (PKA) in the late phase of long-term potentiation (L-LTP) and memory, we generated transgenic mice that express R(AB), an inhibitory form of the regulatory subunit of PKA, only in the hippocampus and other forebrain regions by using the promoter from the gene encoding Ca2+/ calmodulin protein kinase IIalpha. In these R(AB) transgenic mice, hippocampal PKA activity was reduced, and L-LTP was significantly decreased in area CA1, without affecting basal synaptic transmission or the early phase of LTP. Moreover, the L-LTP deficit was paralleled by behavioral deficits in spatial memory and in long-term but not short-term memory for contextual fear conditioning. These deficits in long-term memory were similar to those produced by protein synthesis inhibition. Thus, PKA plays a critical role in the consolidation of long-term memory.
Abel
T
T
Center for Neurobiology and Behavior, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Nguyen
P V
PV
Barad
M
M
Deuel
T A
TA
Kandel
E R
ER
Bourtchouladze
R
R
D000679:Amygdala / Q000502:physiology; D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D003213:Conditioning, Psychological / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics*; D004558:Electric Stimulation; D005239:Fear / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000201:enzymology*; D017774:Long-Term Potentiation / Q000235:genetics*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016548:Prosencephalon / Q000201:enzymology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012153:Retention, Psychology / Q000187:drug effects / Q000502:physiology*; D013037:Spatial Behavior / Q000502:physiology; D013569:Synapses / Q000502:physiology; D013649:Taste / Q000502:physiology
D011500:Protein Synthesis Inhibitors; D000841:Anisomycin; D017868:Cyclic AMP-Dependent Protein Kinases