Chronically increased Gsalpha signaling disrupts associative and spatial learning.
The cAMP/PKA pathway plays a critical role in learning and memory systems in animals ranging from mice to Drosophila to Aplysia. Studies of olfactory learning in Drosophila suggest that altered expression of either positive or negative regulators of the cAMP/PKA signaling pathway beyond a certain optimum range may be deleterious. Here we provide genetic evidence of the behavioral and physiological effects of increased signaling through the cAMP/PKA pathway in mice. We have generated transgenic mice in which the expression of a constitutively active form of Gsalpha (Gsalpha* Q227L), the G protein that stimulates adenylyl cyclase activity, is driven in neurons within the forebrain by the promoter from the CaMKIIalpha gene. Despite significantly increased adenylyl cyclase activity, Gsalpha* transgenic mice exhibit PKA-dependent decreases in levels of cAMP due to a compensatory up-regulation in phosphodiesterase activity. Interestingly, Gsalpha* transgenic mice also exhibit enhanced basal synaptic transmission. Consistent with a role for the cAMP/PKA pathway in learning and memory, Gsalpha* transgenic mice show impairments in spatial learning in the Morris water maze and in contextual and cued fear conditioning tasks. The learning deficits observed in these transgenic mice suggest that associative and spatial learning requires regulated Gsalpha protein signaling, much as does olfactory learning in Drosophila.
Bourtchouladze
Rusiko
R
Center for Neurobiology and Behavior and Howard Hughes Medical Institute, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Patterson
Susan L
SL
Kelly
Michele P
MP
Kreibich
Arati
A
Kandel
Eric R
ER
Abel
Ted
T
D000262:Adenylyl Cyclases / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001245:Association Learning / Q000502:physiology*; D003214:Conditioning, Classical / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005239:Fear / Q000502:physiology; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics / Q000378:metabolism*; D008297:Male; D018782:Maze Learning / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000201:enzymology; D016548:Prosencephalon / Q000201:enzymology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013037:Spatial Behavior / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology; D015854:Up-Regulation
D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019205:GTP-Binding Protein alpha Subunits, Gs; D000262:Adenylyl Cyclases