TY - JOUR
T1 - Forebrain-specific constitutively active CaMKKα transgenic mice show deficits in hippocampus-dependent long-term memory
AU - Kaitsuka, Taku
AU - Li, Sheng Tian
AU - Nakamura, Kenji
AU - Takao, Keizo
AU - Miyakawa, Tsuyoshi
AU - Matsushita, Masayuki
N1 - Funding Information:
We thank T. Hino of the Mouse Genome Technology Center at MITILS for generating CaMKKc tg mice, and S. Kamijo and M. Matsuo for breeding and maintaining the transgenic mice. We also thank N. Kojima for the pNN265 and pNN279 vectors, and N. Nozaki for the anti-phosphorylated CaMKI antibody. This work was supported by Integrative Brain Research (IBR-shien) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.
PY - 2011/9
Y1 - 2011/9
N2 - The Ca 2+/calmodulin (CaM) kinase cascade is activated by Ca 2+ influx through the voltage-dependent Ca 2+ channels and the NMDA receptor. CaM kinase kinase (CaMKK), the most upstream kinase of the CaM kinase cascade, phosphorylates and activates both CaM kinase I (CaMKI) and CaMKIV, resulting in activation of cyclic AMP-responsive element binding protein (CREB)-dependent gene transcription. Using transgenic techniques, we created mutant mice in which a constitutively active form of CaMKK1, the autoinhibitory domain truncated protein, is over-expressed specifically in the forebrain. In these mice, although performance was normal in basal activity and short-term memory, specific impairments were shown in hippocampus-dependent long-term memory after training in spatial memory tasks and after contextual fear conditioning. In cultured neurons of these mice, phosphorylation of CaMKI was significantly increased in basal states, whereas the activity range of CaMKI phosphorylation by brain-derived neurotrophic factor (BDNF) and KCl stimulation was significantly diminished in mutant mice. Our results define a critical role for CaMKKα in synaptic plasticity and the retention of hippocampus-dependent long-term memory.
AB - The Ca 2+/calmodulin (CaM) kinase cascade is activated by Ca 2+ influx through the voltage-dependent Ca 2+ channels and the NMDA receptor. CaM kinase kinase (CaMKK), the most upstream kinase of the CaM kinase cascade, phosphorylates and activates both CaM kinase I (CaMKI) and CaMKIV, resulting in activation of cyclic AMP-responsive element binding protein (CREB)-dependent gene transcription. Using transgenic techniques, we created mutant mice in which a constitutively active form of CaMKK1, the autoinhibitory domain truncated protein, is over-expressed specifically in the forebrain. In these mice, although performance was normal in basal activity and short-term memory, specific impairments were shown in hippocampus-dependent long-term memory after training in spatial memory tasks and after contextual fear conditioning. In cultured neurons of these mice, phosphorylation of CaMKI was significantly increased in basal states, whereas the activity range of CaMKI phosphorylation by brain-derived neurotrophic factor (BDNF) and KCl stimulation was significantly diminished in mutant mice. Our results define a critical role for CaMKKα in synaptic plasticity and the retention of hippocampus-dependent long-term memory.
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U2 - 10.1016/j.nlm.2011.04.017
DO - 10.1016/j.nlm.2011.04.017
M3 - Article
C2 - 21558011
AN - SCOPUS:79960843388
SN - 1074-7427
VL - 96
SP - 238
EP - 247
JO - Neurobiology of Learning and Memory
JF - Neurobiology of Learning and Memory
IS - 2
ER -