Cdk5/p35 functions as a crucial regulator of spatial learning and memory

Tomohide Mishiba; Mika Tanaka; Naoki Mita; Xiaojuan He; Kodai Sasamoto; Shigeyoshi Itohara; Toshio Ohshima

doi:10.1186/s13041-014-0082-x

Cdk5/p35 functions as a crucial regulator of spatial learning and memory

Mol Brain. 2014 Nov 18:7:82. doi: 10.1186/s13041-014-0082-x.

Authors

Tomohide Mishiba¹, Mika Tanaka², Naoki Mita³, Xiaojuan He⁴, Kodai Sasamoto⁵, Shigeyoshi Itohara⁶, Toshio Ohshima⁷

Affiliations

¹ Laboratory for Molecular Brain Science, Department of Life Science and Medical Bioscience, Waseda University, 2-2 Wakamatsu-cho, , Shinjuku-ku, Tokyo, 162-8480, Japan. sprewell-tomo348@akane.waseda.jp.
² Laboratory for Behavioral Genetics, Brain Science Institute, RIKEN, Saitama, 351-0198, Japan. mikatanaka@brain.riken.jp.
³ Laboratory for Molecular Brain Science, Department of Life Science and Medical Bioscience, Waseda University, 2-2 Wakamatsu-cho, , Shinjuku-ku, Tokyo, 162-8480, Japan. mitanaoki@fuji.waseda.jp.
⁴ Laboratory for Molecular Brain Science, Department of Life Science and Medical Bioscience, Waseda University, 2-2 Wakamatsu-cho, , Shinjuku-ku, Tokyo, 162-8480, Japan. jane@suou.waseda.jp.
⁵ Laboratory for Molecular Brain Science, Department of Life Science and Medical Bioscience, Waseda University, 2-2 Wakamatsu-cho, , Shinjuku-ku, Tokyo, 162-8480, Japan. amethyst-ks.46@toki.waseda.jp.
⁶ Laboratory for Behavioral Genetics, Brain Science Institute, RIKEN, Saitama, 351-0198, Japan. sitohara@brain.riken.jp.
⁷ Laboratory for Molecular Brain Science, Department of Life Science and Medical Bioscience, Waseda University, 2-2 Wakamatsu-cho, , Shinjuku-ku, Tokyo, 162-8480, Japan. ohshima@waseda.jp.

Abstract

Background: Cyclin-dependent kinase 5 (Cdk5), which is activated by binding to p35 or p39, is involved in synaptic plasticity and affects learning and memory formation. In Cdk5 knockout (KO) mice and p35 KO mice, brain development is severely impaired because neuronal migration is impaired and lamination is disrupted. To avoid these developmental confounders, we generated inducible CreER-p35 conditional (cKO) mice to study the role of Cdk5/p35 in higher brain function.

Results: CreER-p35 cKO mice exhibited spatial learning and memory impairments and reduced anxiety-like behavior. These phenotypes resulted from a decrease in the dendritic spine density of CA1 pyramidal neurons and defective long-term depression induction in the hippocampus.

Conclusions: Taken together, our findings reveal that Cdk5/p35 regulates spatial learning and memory, implicating Cdk5/p35 as a therapeutic target in neurological disorders.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Animals
Anxiety / metabolism
Anxiety / physiopathology
Cyclin-Dependent Kinase 5 / deficiency
Cyclin-Dependent Kinase 5 / metabolism*
Dendritic Spines / drug effects
Dendritic Spines / metabolism
Integrases / metabolism
Long-Term Synaptic Depression / drug effects
Male
Memory*
Mice, Inbred C57BL
Mice, Knockout
Motor Activity / drug effects
Phosphorylation / drug effects
Phosphotransferases / deficiency
Phosphotransferases / metabolism*
Pyramidal Cells / drug effects
Pyramidal Cells / metabolism
Receptors, Estrogen / metabolism
Receptors, Metabotropic Glutamate / metabolism
Spatial Learning*
Synapses / drug effects
Synapses / metabolism
Synaptic Transmission / drug effects
Tamoxifen / administration & dosage
Tamoxifen / pharmacology

Substances

Cdk5r1 protein, mouse
Receptors, Estrogen
Receptors, Metabotropic Glutamate
metabotropic glutamate receptor type 1
Tamoxifen
Phosphotransferases
Cyclin-Dependent Kinase 5
Cdk5 protein, mouse
Cre recombinase
Integrases