title: Striatal dysregulation of Cdk5 alters locomotor responses to cocaine, motor learning, and dendritic morphology.
abstract: Motor learning and neuro-adaptations to drugs of abuse rely upon neuronal signaling in the striatum. Cyclin-dependent kinase 5 (Cdk5) regulates striatal dopamine neurotransmission and behavioral responses to cocaine. Although the role for Cdk5 in neurodegeneration in the cortex and hippocampus and in hippocampal-dependent learning has been demonstrated, its dysregulation in the striatum has not been examined. Here we show that strong activation of striatal NMDA receptors produced p25, the truncated form of the Cdk5 co-activator p35. Furthermore, inducible overexpression of p25 in the striatum prevented locomotor sensitization to cocaine and attenuated motor coordination and learning. This corresponded with reduced dendritic spine density, increased neuro-inflammation, altered dopamine signaling, and shifted Cdk5 specificity with regard to physiological and aberrant substrates, but no apparent loss of striatal neurons. Thus, dysregulation of Cdk5 dramatically affects striatal-dependent brain function and may be relevant to non-neurodegenerative disorders involving dopamine neurotransmission.
authors.affiliation: Departments of Psychiatry and Radiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9070, USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Meyer
authors.forename: Edmond
authors.initials: E
authors.lastname: Richer
authors.forename: Stanley A
authors.initials: SA
authors.lastname: Benkovic
authors.forename: Kanehiro
authors.initials: K
authors.lastname: Hayashi
authors.forename: Janice W
authors.initials: JW
authors.lastname: Kansy
authors.forename: Carly F
authors.initials: CF
authors.lastname: Hale
authors.forename: Lily Y
authors.initials: LY
authors.lastname: Moy
authors.forename: Yong
authors.initials: Y
authors.lastname: Kim
authors.forename: James P
authors.initials: JP
authors.lastname: O'Callaghan
authors.forename: Li-Huei
authors.initials: LH
authors.lastname: Tsai
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
authors.forename: Angus C
authors.initials: AC
authors.lastname: Nairn
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Cowan
authors.forename: Diane B
authors.initials: DB
authors.lastname: Miller
authors.forename: Pietro
authors.initials: P
authors.lastname: Antich
authors.forename: James A
authors.initials: JA
authors.lastname: Bibb
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D003042:Cocaine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000502:physiology*; D003712:Dendrites / Q000187:drug effects* / Q000502:physiology; D007858:Learning; D008124:Locomotion; D051379:Mice; D008822:Mice, Transgenic; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D003042:Cocaine