Control of memory formation through regulated expression of a CaMKII transgene.
One of the major limitations in the use of genetically modified mice for studying cognitive functions is the lack of regional and temporal control of gene function. To overcome these limitations, a forebrain-specific promoter was combined with the tetracycline transactivator system to achieve both regional and temporal control of transgene expression. Expression of an activated calcium-independent form of calcium-calmodulin-dependent kinase II (CaMKII) resulted in a loss of hippocampal long-term potentiation in response to 10-hertz stimulation and a deficit in spatial memory, a form of explicit memory. Suppression of transgene expression reversed both the physiological and the memory deficit. When the transgene was expressed at high levels in the lateral amygdala and the striatum but not other forebrain structures, there was a deficit in fear conditioning, an implicit memory task, that also was reversible. Thus, the CaMKII signaling pathway is critical for both explicit and implicit memory storage, in a manner that is independent of its potential role in development.
Mayford
M
M
Center for Neurobiology and Behavior, College of Physicians and Surgeons of Columbia University, and Howard Hughes Medical Institute, 722 West 168 Street, New York, NY 10032, USA.
Bach
M E
ME
Huang
Y Y
YY
Wang
L
L
Hawkins
R D
RD
Kandel
E R
ER
D000679:Amygdala / Q000502:physiology; D000818:Animals; D001921:Brain / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D003213:Conditioning, Psychological; D003342:Corpus Striatum / Q000502:physiology; D004318:Doxycycline / Q000494:pharmacology; D005239:Fear; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D006624:Hippocampus / Q000502:physiology; D017774:Long-Term Potentiation; D018782:Maze Learning; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009473:Neuronal Plasticity; D011401:Promoter Regions, Genetic; D016548:Prosencephalon / Q000502:physiology; D015398:Signal Transduction; D019076:Transgenes
D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D004318:Doxycycline