Impairment of hippocampal long-term depression and defective spatial learning and memory in p35 mice.
Cdk5 (cyclin-dependent kinase 5) activity is dependent upon association with one of two neuron-specific activators, p35 or p39. Genetic deletion of Cdk5 causes perinatal lethality with severe defects in corticogenesis and neuronal positioning. p35(-/-) mice are viable with milder histological abnormalities. Although substantial evidence implicates Cdk5 in synaptic plasticity, its role in learning and memory has not been evaluated using mutant mouse models. We report here that p35(-/-) mice have deficiencies in spatial learning and memory. Close examination of hippocampal circuitry revealed subtle histological defects in CA1 pyramidal cells. Furthermore, p35(-/-) mice exhibit impaired long-term depression and depotentiation of long-term potentiation in the Schaeffer collateral CA1 pathway. Moreover, the Cdk5-dependent phosphorylation state of protein phosphatase inhibitor-1 was increased in 4-week-old mice due to increased levels of p39, which co-localized with inhibitor-1 and Cdk5 in the cytoplasm. These results demonstrate that p35-dependent Cdk5 activity is important to learning and synaptic plasticity. Deletion of p35 may shift the substrate specificity of Cdk5 due to compensatory expression of p39.
Laboratory for Developmental Neurobiology, Brain Science Institute, Hirosawa, Wako-City, Saitama, Japan. ohshima@brain.riken.go.jp
Toshio
T
Ohshima
Hiroo
H
Ogura
Kazuhito
K
Tomizawa
Kanehiro
K
Hayashi
Hiromi
H
Suzuki
Taro
T
Saito
Hirotsugu
H
Kamei
Akinori
A
Nishi
James A
JA
Bibb
Shin-Ichi
S
Hisanaga
Hideki
H
Matsui
Katsuhiko
K
Mikoshiba
D000595:Amino Acid Sequence; D000818:Animals; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000502:physiology* / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D018782:Maze Learning / Q000502:physiology*; D008568:Memory / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009473:Neuronal Plasticity; D010766:Phosphorylation; D010770:Phosphotransferases / Q000172:deficiency / Q000502:physiology*; D013569:Synapses
C492236:Cdk5r1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C021042:protein phosphatase inhibitor-1; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D018844:Cyclin-Dependent Kinases