title: Forebrain-specific deletion of Cdk5 in pyramidal neurons results in mania-like behavior and cognitive impairment.
abstract: Cyclin-dependent kinase 5 (Cdk5) is associated with synaptic plasticity and cognitive function. Previous reports have demonstrated that Cdk5 is necessary for memory formation, although others have reported Cdk5 conditional knockout mouse models exhibiting enhanced learning and memory. Furthermore, how Cdk5 acts in specific cell populations to affect behavior and cognitive outcomes remains unclear. Here we conduct a behavioral characterization of a forebrain-specific Cdk5 conditional knockout mouse model under the αCaMKII promoter, in which Cdk5 is ablated in excitatory pyramidal neurons of the forebrain. The Cdk5 conditional knockouts exhibit hyperactivity in the open field, reduced anxiety, and reduced behavioral despair. Moreover, the Cdk5 conditional knockouts also display impaired spatial learning in the Morris water maze and are severely impaired in contextual fear memory, which correspond to deficits in synaptic transmission. Remarkably, the hyperactivity of the Cdk5 conditional knockouts can be ameliorated by the administration of lithium chloride, an inhibitor of GSK3β signaling. Collectively, our data reveal that Cdk5 ablation from forebrain excitatory neurons results in deleterious effects on emotional and cognitive behavior and highlight a key role for Cdk5 in regulating the GSK3β signaling pathway.
authors.affiliation: The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, United States; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA, United States.
authors.forename: Susan C
authors.initials: SC
authors.lastname: Su
authors.forename: Andrii
authors.initials: A
authors.lastname: Rudenko
authors.forename: Sukhee
authors.initials: S
authors.lastname: Cho
authors.forename: Li-Huei
authors.initials: LH
authors.lastname: Tsai
mesh_terms: D000818:Animals; D003071:Cognition; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D055786:Gene Knockout Techniques; D006948:Hyperkinesis / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016548:Prosencephalon / Q000378:metabolism*; D017966:Pyramidal Cells / Q000378:metabolism*
chemical_list: D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse
keywords: Cdk5; Cognitive function; Hyperactivity; Lithium; Open field; Transmitter release