t 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. Citation: Guan J-S, Su SC, Gao J, 
Joseph N, Xie Z, et al. Cdk5 Is Required for Memory Function and Hippocampal Plasticity via the cAMP Signaling Pathway. PLoS ONE 6: e25735. doi:10.1371/journal.pone.0025735 Editor: Brahim Nait-Oumesmar, Universite Pierre et Marie Curie-Paris6, INSERM, CNRS, France Received June 22, 2011; Accepted September 9, 2011; Published September 30, 2011 Copyright: 2011 Guan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: S.C.S. was supported by NIH T32 MH074249 and a Norman B. Leventhal fellowship. This work is supported by NIH RO1 NS051874. L.-H. T. is an investigator of the Howard Hughes Medical indoleamine-2,3-dioxygenase inhibitor INCB024360 Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. E-mail: [email protected]. These authors contributed equally to this manuscript. Current address: School of Life Sciences, Tsinghua University, Beijing, China Introduction The hippocampus is considered to be a key region “23303071 for long-term memory formation in humans and rodents, yet the molecular mechanisms underlying memory formation are still not fully understood. Transgenic mouse studies using hippocampal regionspecific knockout of the NMDA receptor NR1 subunit strongly support the hypothesis that synaptic plasticity, especially NMDARmediated synaptic plasticity, is crucial for normal learning and memory. Numerous genetic and molecular studies have revealed that NMDAR activation, and its downstream cascade of events, are critical for synaptic plasticity. These events include calcium entry, autophosphorylation of CaMKII, activation of protein phosphatases, and the relocation and modification of AMPA receptors. Perturbations in the molecular cascade downstream of the NMDAR pathway result in defects in both longterm potentiation and memory formation. Blocking the NMDAR pathway, in addition, impacts long-term depression. Interestingly, the PKC gamma mutant mouse, which displays normal LTD and impaired LTP, exhibits a relatively mild behavioral deficit. Thus, both forms of synaptic plasticity are required for memory formation. The cyclic AMP pathway is also critically involved in synaptic plasticity and learning and memory. The second messenger cAMP, as well as the cAMP-dependent protein kinase A, have been implicated in short- and long-lasting synaptic plasticity and intrinsic neuronal excitability in Aplysia by activating cAMP-responsive element binding protein -dependent transcription. Accumulating data regarding the molecular events underlying CREB-dependent learning and memory in Drosophila, mice, and rats “ 24786787 all indicate that CREB activation by phosphorylation at the Serine 133 residue is required for the maintenance of LTP and formation of long-term memory. The maintenance of LTP and long-term memory are also both dependent on PKA activity and CREB-mediated transcription. Cyclic nucleotide phophodieste
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