Transgenic calmodulin-dependent protein kinase II activation: dose-dependent effects on synaptic plasticity, learning, and memory.
Genetic disruption of calmodulin-dependent protein kinase II (CaMKII) function alters hippocampal synaptic plasticity and memory in mice. We used transgenic mice carrying a tetracycline-regulated, calcium-independent form of CaMKII (CaMKII-Asp286) to investigate the role of CaMKII activation on synaptic plasticity and behavior. Mice expressing low levels of a CaMKII-Asp286 transgene have facilitated low-frequency (5 Hz)-induced long-term potentiation (LTP), whereas mice with high levels of transgene expression have a deficit in this form of plasticity. Behavioral impairments on fear-conditioned memory and visible water maze correlate with the level of CaMKII-Asp286 expression. Mice with high levels of CaMKII-Asp286 have reversible, compensatory changes in the expression of genes associated with inhibitory neurotransmission. These results demonstrate that in the hippocampus, CaMKII activation facilitates the induction of low-frequency LTP, but at high levels of expression, compensatory mechanisms act to inhibit the induction of this form of LTP. The most severe behavioral impairments are associated with activation of this compensatory mechanism.
Bejar
Rafael
R
Neurosciences Graduate Program, University of California at San Diego, La Jolla, California 92093, USA.
Yasuda
Rie
R
Krugers
Harmen
H
Hood
Kristin
K
Mayford
Mark
M
D000818:Animals; D001224:Aspartic Acid / Q000235:genetics; D001522:Behavior, Animal; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics* / Q000378:metabolism*; D004789:Enzyme Activation; D007700:Kinetics; D007858:Learning; D017774:Long-Term Potentiation; D018782:Maze Learning; D008568:Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000096:biosynthesis; D009435:Synaptic Transmission; D013752:Tetracycline / Q000494:pharmacology
D012333:RNA, Messenger; D001224:Aspartic Acid; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D013752:Tetracycline