Cdk5 is required for memory function and hippocampal plasticity via the cAMP signaling pathway

• Published in: PloS one 2011-09, Vol.6 (9), p.e25735-e25735
• Main Authors: Guan, Ji-Song, Su, Susan C, Gao, Jun, Joseph, Nadine, Xie, Zhigang, Zhou, Ying, Durak, Omer, Zhang, Lei, Zhu, J Julius, Clauser, Karl R, Carr, Steven A, Tsai, Li-Huei
• Format: Article
• Language: English
• Subjects: Aberration; Animals; Biology; Blotting, Southern; Brain research; Cell cycle; Cyclic adenosine monophosphate; Cyclic AMP - metabolism; Cyclic AMP response element-binding protein; Cyclin-dependent kinase 5; Cyclin-Dependent Kinase 5 - genetics; Cyclin-Dependent Kinase 5 - metabolism; Cyclin-dependent kinases; Electrophysiology; Hippocampal plasticity; Hippocampus; Hippocampus - metabolism; Homeostatic plasticity; Immunoblotting; Immunohistochemistry; Inhibitors; Kinases; Mass spectrometry; Maze Learning; Medicine; Memory; Memory - physiology; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Neuronal Plasticity - genetics; Neuronal Plasticity - physiology; Neurons; Phosphodiesterase; Phosphorylation; Plasticity; Protein kinase; Protein kinase C; Protein kinases; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Rolipram; Scientific imaging; Signal transduction; Signal Transduction - genetics; Signal Transduction - physiology; Signaling; Social and Behavioral Sciences; Substrates; Synaptic plasticity
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0025735

Memory formation is modulated by pre- and post-synaptic signaling events in neurons. The neuronal protein kinase Cyclin-Dependent Kinase 5 (Cdk5) phosphorylates a variety of synaptic substrates and is implicated in memory formation. It has also been shown to play a role in homeostatic regulation of synaptic plasticity in cultured neurons. Surprisingly, we found that Cdk5 loss of function in hippocampal circuits results in severe impairments in memory formation and retrieval. Moreover, Cdk5 loss of function in the hippocampus disrupts cAMP signaling due to an aberrant increase in phosphodiesterase (PDE) proteins. Dysregulation of cAMP is associated with defective CREB phosphorylation and disrupted composition of synaptic proteins in Cdk5-deficient mice. Rolipram, a PDE4 inhibitor that prevents cAMP depletion, restores synaptic plasticity and memory formation in Cdk5-deficient mice. Collectively, our results demonstrate a critical role for Cdk5 in the regulation of cAMP-mediated hippocampal functions essential for synaptic plasticity and memory formation.