Kinase-dead knock-in mouse reveals an essential role of kinase activity of Ca2+/calmodulin-dependent protein kinase IIalpha in dendritic spine enlargement, long-term potentiation, and learning.
Ca2+/calmodulin-dependent protein kinase IIalpha (CaMKIIalpha) is an essential mediator of activity-dependent synaptic plasticity that possesses multiple protein functions. So far, the autophosphorylation site-mutant mice targeted at T286 and at T305/306 have demonstrated the importance of the autonomous activity and Ca2+/calmodulin-binding capacity of CaMKIIalpha, respectively, in the induction of long-term potentiation (LTP) and hippocampus-dependent learning. However, kinase activity of CaMKIIalpha, the most essential enzymatic function, has not been genetically dissected yet. Here, we generated a novel CaMKIIalpha knock-in mouse that completely lacks its kinase activity by introducing K42R mutation and examined the effects on hippocampal synaptic plasticity and behavioral learning. In homozygous CaMKIIalpha (K42R) mice, kinase activity was reduced to the same level as in CaMKIIalpha-null mice, whereas CaMKII protein expression was well preserved. Tetanic stimulation failed to induce not only LTP but also sustained dendritic spine enlargement, a structural basis for LTP, at the Schaffer collateral-CA1 synapse, whereas activity-dependent postsynaptic translocation of CaMKIIalpha was preserved. In addition, CaMKIIalpha (K42R) mice showed a severe impairment in inhibitory avoidance learning, a form of memory that is dependent on the hippocampus. These results demonstrate that kinase activity of CaMKIIalpha is a common critical gate controlling structural, functional, and behavioral expression of synaptic memory.
Yamagata
Yoko
Y
Department of Information Physiology, National Institute for Physiological Sciences, Okazaki 444-8787, Japan. yamagata@nips.ac.jp
Kobayashi
Shizuka
S
Umeda
Tatsuya
T
Inoue
Akihiro
A
Sakagami
Hiroyuki
H
Fukaya
Masahiro
M
Watanabe
Masahiko
M
Hatanaka
Nobuhiko
N
Totsuka
Masako
M
Yagi
Takeshi
T
Obata
Kunihiko
K
Imoto
Keiji
K
Yanagawa
Yuchio
Y
Manabe
Toshiya
T
Okabe
Shigeo
S
D000818:Animals; D001362:Avoidance Learning / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000201:enzymology* / Q000502:physiology / Q000648:ultrastructure; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005260:Female; D055879:Gene Knock-In Techniques; D006624:Hippocampus / Q000201:enzymology* / Q000502:physiology; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020125:Mutation, Missense; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000201:enzymology* / Q000502:physiology; D013569:Synapses / Q000201:enzymology / Q000502:physiology
D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C517671:Camk2a protein, mouse