Cdk5 Is Required for Memory Function and Hippocampal Plasticity via the cAMP Signaling Pathway
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{"title"=>"Cdk5 is required for memory function and hippocampal plasticity via the camp signaling pathway", "type"=>"journal", "authors"=>[{"first_name"=>"Ji Song", "last_name"=>"Guan", "scopus_author_id"=>"8661275200"}, {"first_name"=>"Susan C.", "last_name"=>"Su", "scopus_author_id"=>"7402030109"}, {"first_name"=>"Jun", "last_name"=>"Gao", "scopus_author_id"=>"57198100562"}, {"first_name"=>"Nadine", "last_name"=>"Joseph", "scopus_author_id"=>"26535987900"}, {"first_name"=>"Zhigang", "last_name"=>"Xie", "scopus_author_id"=>"36740485900"}, {"first_name"=>"Ying", "last_name"=>"Zhou", "scopus_author_id"=>"55718569400"}, {"first_name"=>"Omer", "last_name"=>"Durak", "scopus_author_id"=>"26030369700"}, {"first_name"=>"Lei", "last_name"=>"Zhang", "scopus_author_id"=>"36063274500"}, {"first_name"=>"J. Julius", "last_name"=>"Zhu", "scopus_author_id"=>"35228243900"}, {"first_name"=>"Karl R.", "last_name"=>"Clauser", "scopus_author_id"=>"6602911756"}, {"first_name"=>"Steven A.", "last_name"=>"Carr", "scopus_author_id"=>"7202363695"}, {"first_name"=>"Li Huei", "last_name"=>"Tsai", "scopus_author_id"=>"7203033461"}], "year"=>2011, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-80053582153", "pmid"=>"21984943", "sgr"=>"80053582153", "doi"=>"10.1371/journal.pone.0025735", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "issn"=>"19326203", "pui"=>"362706603"}, "id"=>"0675d55e-e3be-3b65-96a6-518b40c500db", "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.", "link"=>"http://www.mendeley.com/research/cdk5-required-memory-function-hippocampal-plasticity-via-camp-signaling-pathway", "reader_count"=>55, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>4, "Researcher"=>16, "Student > Doctoral Student"=>4, "Student > Ph. D. Student"=>10, "Student > Postgraduate"=>3, "Student > Master"=>6, "Other"=>3, "Student > Bachelor"=>5, "Professor"=>4}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>4, "Researcher"=>16, "Student > Doctoral Student"=>4, "Student > Ph. D. Student"=>10, "Student > Postgraduate"=>3, "Student > Master"=>6, "Other"=>3, "Student > Bachelor"=>5, "Professor"=>4}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>1, "Agricultural and Biological Sciences"=>28, "Medicine and Dentistry"=>11, "Neuroscience"=>9, "Psychology"=>2, "Computer Science"=>2, "Unspecified"=>1, "Chemistry"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>11}, "Neuroscience"=>{"Neuroscience"=>9}, "Chemistry"=>{"Chemistry"=>1}, "Psychology"=>{"Psychology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>28}, "Computer Science"=>{"Computer Science"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}, "Unspecified"=>{"Unspecified"=>1}}, "reader_count_by_country"=>{"United States"=>2, "Chile"=>1, "Kazakhstan"=>1}, "group_count"=>4}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/729523"], "description"=>"<p><b>A</b>. Acute hippocampal slices obtained from 2-month-old Cdk5f/f/T29 and Cdk5f/f mice were stimulated with two trains of HFS (100 Hz, 1 s) in area CA1. Field EPSPs (fEPSPs) were measured from area CA1 in Cdk5f/f and Cdk5f/f/T29 mice (n = 8 for each group). <b>B</b>. Paired-pulse facilitation (PPF) in Cdk5f/f mice and Cdk5f/f/T29 and (n = 9 for each group). <b>C</b>. The input-output curve indicates normal basal synaptic transmission in the Cdk5f/f/T29 mice. <b>D.</b> Post-tetanic potentiation (PTP) from Cdk5f/f/T29 mice was lower than in Cdk5f/f mice 30 s after two trains of HFS (100 Hz, 1 s). <b>E</b>. LTD was measured in area CA1 of acute hippocampal slices from Cdk5f/f and Cdk5f/f/T29 after low frequency stimulation (1 Hz, 900 pulse; n = 6 for each group).</p>", "links"=>[], "tags"=>["plasticity", "impaired"], "article_id"=>399870, "categories"=>["Physiology", "Molecular Biology", "Neuroscience", "Mental Health"], "users"=>["Ji-Song Guan", "Susan C. Su", "Jun Gao", "Nadine Joseph", "Zhigang Xie", "Ying Zhou", "Omer Durak", "Lei Zhang", "J. Julius Zhu", "Karl R. Clauser", "Steven A. Carr", "Li-Huei Tsai"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025735.g003", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Synaptic_plasticity_is_largely_impaired_in_Cdk5f_f_T29_mice_/399870", "title"=>"Synaptic plasticity is largely impaired in Cdk5f/f/T29 mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-09-30 02:44:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/730030"], "description"=>"<p><b>A</b>. Western blot from CA1 lysates after rolipram treatment. Samples were collected 20 min after rolipram or saline (control) injection. <b>B</b>. PP1 activity in area CA1 tissue was measured after rolipram treatment (0.1 mg/kg, i.p.). <b>C</b>. Western blots (left) for CA1 tissues from Cdk5f/f mice, with quantification (right). Mice were trained in a contextual fear conditioning paradigm followed by tissue harvest 20 min after training. n = 5 for each group. <b>D</b>. Western blots (left) from micro-dissected CA1 tissues from Cdk5f/f/T29 mice with quantification (right). Rolipram (0.1 mg/kg, i.p.) was injected 20 min before contextual fear conditioning training. Samples were collected 20 min after training (n = 3 for each group). <b>E</b>. Rolipram restored LTP deficits in the Cdk5f/f/T29 slices. Mice were injected with rolipram or vehicle (Veh) 20 min before sacrifice and slice preparation. Rolipram was also present in the bath solution at 0.7 µM. Slices were stimulated with two trains of HFS (100 Hz, 1 s; n = 6 for each group; *<i>p</i><0.05, between vehicle- and rolipram-treated groups in Cdk5f/f/T29 mice). <b>F</b>. Rolipram did not rescue the LTD impairment in Cdk5f/f/T29 slices (n = 5 for each group). <b>G</b>. In a contextual fear conditioning task, the percent of time spent freezing in Cdk5f/f/T29 mice (n = 16) is significantly lower than that of control Cdk5f/f mice (n = 8). The percent freezing time for the Cdk5f/f/T29 mice injected with rolipram (0.1 mg/kg, i.p.) 20 min before training (n = 8) or 3 hr after training (n = 7) is similar to that of the control Cdk5 f/f mice.</p>", "links"=>[], "tags"=>["pde4", "rolipram", "ltp", "deficits", "impairments"], "article_id"=>400364, "categories"=>["Physiology", "Molecular Biology", "Neuroscience", "Mental Health"], "users"=>["Ji-Song Guan", "Susan C. Su", "Jun Gao", "Nadine Joseph", "Zhigang Xie", "Ying Zhou", "Omer Durak", "Lei Zhang", "J. Julius Zhu", "Karl R. Clauser", "Steven A. Carr", "Li-Huei Tsai"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025735.g006", "stats"=>{"downloads"=>1, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inhibition_of_PDE4_by_rolipram_can_restore_LTP_deficits_and_rescue_memory_impairments_in_Cdk5f_f_T29_mice_/400364", "title"=>"Inhibition of PDE4 by rolipram can restore LTP deficits and rescue memory impairments in Cdk5f/f/T29 mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-09-30 00:06:04"}
  • {"files"=>["https://ndownloader.figshare.com/files/729241"], "description"=>"<p><b>A</b>. Immunostaining for Cdk5 in hippocampal areas CA1 and CA3 in Cdk5f/f, Cdk5f/f/T29 mice. Scale bars, 100 µm. <b>B</b>. Western blot showing the reduction of Cdk5 in micro-dissected area CA1 of Cdk5f/f/T29 mice. <b>C</b>. Context- and tone-dependent (cued) fear conditioning tests for Cdk5f/f/T29 and Cdk5f/f (control) mice. Cdk5f/f, n = 16; Cdk5f/f/T29, n = 16 for context; Cdk5f/f, n = 8; Cdk5f/f/T29 n = 8 for tone-dependent task. <b>D</b>. Distance traveled during the initial 3 min exposure to the training box. <b>E</b>. The velocity during the 3 min of training and electrical foot shock. <b>F</b>. In context-dependent fear conditioning test, Cdk5f/f and Cdk5f/f/T29 mice were trained for 3 continuous days. Cdk5f/f, n = 8; Cdk5f/f/T29, n = 8. <b>G</b>. Morris water maze test. Escape latencies of Cdk5f/f mice improved significantly faster than Cdk5f/f/T29 mice. N = 8 for each group. <b>H</b>. On day 7, a probe trial was conducted in which the swimming time in each quadrant was quantified. T, target quadrant; L, left quadrant; O, opposite quadrant; R, right quadrant. *<i>p</i><0.05; **<i>p</i><0.005; ***<i>p</i><0.001.</p>", "links"=>[], "tags"=>["spatial", "impaired"], "article_id"=>399581, "categories"=>["Physiology", "Molecular Biology", "Neuroscience", "Mental Health"], "users"=>["Ji-Song Guan", "Susan C. Su", "Jun Gao", "Nadine Joseph", "Zhigang Xie", "Ying Zhou", "Omer Durak", "Lei Zhang", "J. Julius Zhu", "Karl R. Clauser", "Steven A. Carr", "Li-Huei Tsai"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025735.g001", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Associative_and_spatial_learning_are_impaired_in_Cdk5f_f_T29_mice_/399581", "title"=>"Associative and spatial learning are impaired in Cdk5f/f/T29 mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-09-30 02:39:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/729683"], "description"=>"<p><b>A–B</b>. Immunostaining (<b>A</b>) and quantification (<b>B</b>) of pCREB in hippocampal CA1 and cortex. Scale bar = 100 µm. <b>C</b>. Western blots of micro-dissected CA1 tissue show reduced pCREB levels. <b>D</b>. Western blots of micro-dissected CA1 tissue reveals hyper-phosphorylation of GluR1. <b>E.</b> Area CA1 phosphatase activity in Cdk5f/f and Cdk5f/f/T29 mice (n = 3, each group). *<i>p</i><0.05, **<i>p</i><0.005, ***<i>p</i><0.001.</p>", "links"=>[], "tags"=>["creb", "phosphorylation", "hyper-phorsphorylation", "glur1"], "article_id"=>400023, "categories"=>["Physiology", "Molecular Biology", "Neuroscience", "Mental Health"], "users"=>["Ji-Song Guan", "Susan C. Su", "Jun Gao", "Nadine Joseph", "Zhigang Xie", "Ying Zhou", "Omer Durak", "Lei Zhang", "J. Julius Zhu", "Karl R. Clauser", "Steven A. Carr", "Li-Huei Tsai"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025735.g004", "stats"=>{"downloads"=>5, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Impaired_CREB_phosphorylation_and_hyper_phorsphorylation_of_GluR1_in_Cdk5f_f_T29_mice_/400023", "title"=>"Impaired CREB phosphorylation and hyper-phorsphorylation of GluR1 in Cdk5f/f/T29 mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-09-30 00:00:23"}
  • {"files"=>["https://ndownloader.figshare.com/files/729397"], "description"=>"<p><b>A</b>. Immunostaining for Cdk5 in hippocampal areas CA1 and CA3 in Cdk5f/f and Cdk5f/f/KA1 mice. Scale bar, 100 µm. <b>B</b>. Contextual-dependent fear conditioning test for Cdk5f/f/KA1 mice. Cdk5f/f, n = 10; Cdk5f/f/KA1, n = 8. <b>C</b>. Distance traveled during the initial 3 min exposure to the training box. <b>D</b>. Morris water maze training paradigm (top). Mice were trained for 16 days. On day 15, they were tested in a probe trial with full visual cues around the tank, followed by an additional training trial. On day 16, mice were tested in another probe trial with most of the visual cues removed around the tank. (Bottom) Latencies for the mice to reach the platform during training did not show significant differences between Cdk5f/f/KA1 (n = 10) and Cdk5f/f mice (n = 10). (P), partial cues, (F), full cues. <b>E</b>. Cdk5f/f/KA1 mice showed similar preferences toward the target quadrant as the Cdk5f/f group in a full cue trial on day 15. <b>F</b>. Cdk5f/f/KA1 mice did not show preferences toward the target quadrant in the partial-cue-trial on day 16. <b>G</b>. Cdk5f/f/KA1 mice take more time to reach the hidden platform position than Cdk5f/f mice in the partial cue, but not the full cue, trial. <b>H</b>. In the probe trial with partial cues, the average number of crossings over the platform position is much lower for the Cdk5f/f/KA1 group than that for the Cdk5f/f group. *<i>p</i><0.05; **<i>p</i><0.005.</p>", "links"=>[], "tags"=>["retrieval", "impaired"], "article_id"=>399736, "categories"=>["Physiology", "Molecular Biology", "Neuroscience", "Mental Health"], "users"=>["Ji-Song Guan", "Susan C. Su", "Jun Gao", "Nadine Joseph", "Zhigang Xie", "Ying Zhou", "Omer Durak", "Lei Zhang", "J. Julius Zhu", "Karl R. Clauser", "Steven A. Carr", "Li-Huei Tsai"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025735.g002", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Memory_retrieval_is_impaired_in_Cdk5f_f_KA1_mice_/399736", "title"=>"Memory retrieval is impaired in Cdk5f/f/KA1 mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-09-30 02:42:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/368566", "https://ndownloader.figshare.com/files/368624", "https://ndownloader.figshare.com/files/368704", "https://ndownloader.figshare.com/files/368736", "https://ndownloader.figshare.com/files/368762"], "description"=>"<div><p>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.</p> </div>", "links"=>[], "tags"=>["cdk5", "hippocampal", "plasticity", "signaling", "pathway"], "article_id"=>132822, "categories"=>["Physiology", "Molecular Biology", "Neuroscience", "Mental Health"], "users"=>["Ji-Song Guan", "Susan C. Su", "Jun Gao", "Nadine Joseph", "Zhigang Xie", "Ying Zhou", "Omer Durak", "Lei Zhang", "J. Julius Zhu", "Karl R. Clauser", "Steven A. Carr", "Li-Huei Tsai"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0025735.s001", "https://dx.doi.org/10.1371/journal.pone.0025735.s002", "https://dx.doi.org/10.1371/journal.pone.0025735.s003", "https://dx.doi.org/10.1371/journal.pone.0025735.s004", "https://dx.doi.org/10.1371/journal.pone.0025735.s005"], "stats"=>{"downloads"=>6, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Cdk5_Is_Required_for_Memory_Function_and_Hippocampal_Plasticity_via_the_cAMP_Signaling_Pathway/132822", "title"=>"Cdk5 Is Required for Memory Function and Hippocampal Plasticity via the cAMP Signaling Pathway", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2011-09-30 00:47:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/730157"], "description"=>"<p>The mouse strains used for analysis include three genotypes: Cdk5f/f/T29, Cdk5f/f/KA1, and Cdk5 f/f/CW2. Three different Cre promoter lines were used to generate these genotypes by breeding the Cre line to the Cdk5 floxed lines to obtain the CA1, CA3, and forebrain-specific knockdown of Cdk5. In all experiments, 2.5–3.5 month old mice were used, and age-matched littermate Cdk5f/f mice were used as controls.</p>", "links"=>[], "tags"=>["mutant", "strains", "generated"], "article_id"=>400499, "categories"=>["Physiology", "Molecular Biology", "Neuroscience", "Mental Health"], "users"=>["Ji-Song Guan", "Susan C. Su", "Jun Gao", "Nadine Joseph", "Zhigang Xie", "Ying Zhou", "Omer Durak", "Lei Zhang", "J. Julius Zhu", "Karl R. Clauser", "Steven A. Carr", "Li-Huei Tsai"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025735.t001", "stats"=>{"downloads"=>3, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cdk5_mutant_mouse_strains_generated_for_analysis_/400499", "title"=>"Cdk5 mutant mouse strains generated for analysis.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-09-30 00:08:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/729861"], "description"=>"<p><b>A</b>. Procedure sequence for mass-spectrometry analysis with PSDs from control (Cdk5f/f) and Cdk5f/f/CW2 (cKO) mice. <b>B</b>. Summary of detected protein abundance differences categorized by various protein functions. <b>C.</b> Representative molecules changes detected in Cdk5 cKO mice. Red number indicates reduction folds; black number indicates increase folds. <b>D</b>. RT-qPCR results of ACs in hippocampal CA1 in Cdk5f/f and Cdk5f/f/T29. qPCR signals were normalized to actin in each sample (n = 3). <b>E.</b> RT-qPCR results of PDEs from hippocampal area CA1 in Cdk5f/f and Cdk5f/f/T29.</p>", "links"=>[], "tags"=>["post-synaptic", "densities", "reveals", "changes", "pde", "proteins", "cdk5", "mutant"], "article_id"=>400196, "categories"=>["Physiology", "Molecular Biology", "Neuroscience", "Mental Health"], "users"=>["Ji-Song Guan", "Susan C. Su", "Jun Gao", "Nadine Joseph", "Zhigang Xie", "Ying Zhou", "Omer Durak", "Lei Zhang", "J. Julius Zhu", "Karl R. Clauser", "Steven A. Carr", "Li-Huei Tsai"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025735.g005", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Proteomic_analysis_of_post_synaptic_densities_reveals_changes_in_PDE_proteins_in_CDK5_mutant_mice_/400196", "title"=>"Proteomic analysis of post-synaptic densities reveals changes in PDE proteins in CDK5 mutant mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-09-30 00:03:16"}

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