title: Forebrain-specific constitutively active CaMKKα transgenic mice show deficits in hippocampus-dependent long-term memory.
abstract: 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.
authors.affiliation: Mitsubishi Kagaku Institute of Life Sciences (MITILS), 11 Minami-ooya, Machida, Tokyo 194-8511, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Kaitsuka
authors.forename: Sheng-Tian
authors.initials: ST
authors.lastname: Li
authors.forename: Kenji
authors.initials: K
authors.lastname: Nakamura
authors.forename: Keizo
authors.initials: K
authors.lastname: Takao
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Miyakawa
authors.forename: Masayuki
authors.initials: M
authors.lastname: Matsushita
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D005239:Fear / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D008569:Memory Disorders / Q000235:genetics*; D057567:Memory, Long-Term / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation; D016548:Prosencephalon / Q000187:drug effects / Q000502:physiology*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase