title: Cdk5 is required for memory function and hippocampal plasticity via the cAMP signaling pathway.
abstract: 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.
authors: Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors: Ji-Song
authors: JS
authors: Guan
authors: Susan C
authors: SC
authors: Su
authors: Jun
authors: J
authors: Gao
authors: Nadine
authors: N
authors: Joseph
authors: Zhigang
authors: Z
authors: Xie
authors: Ying
authors: Y
authors: Zhou
authors: Omer
authors: O
authors: Durak
authors: Lei
authors: L
authors: Zhang
authors: J Julius
authors: JJ
authors: Zhu
authors: Karl R
authors: KR
authors: Clauser
authors: Steven A
authors: SA
authors: Carr
authors: Li-Huei
authors: LH
authors: Tsai
mesh_terms: D000818:Animals; D015139:Blotting, Southern; D000242:Cyclic AMP / Q000378:metabolism*; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D004594:Electrophysiology; D006624:Hippocampus / Q000378:metabolism*; D015151:Immunoblotting; D007150:Immunohistochemistry; D018782:Maze Learning; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
chemical_list: D000242:Cyclic AMP; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse