Striatal dysregulation of Cdk5 alters locomotor responses to cocaine, motor learning, and dendritic morphology.
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.
Meyer
Douglas A
DA
Departments of Psychiatry and Radiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9070, USA.
Richer
Edmond
E
Benkovic
Stanley A
SA
Hayashi
Kanehiro
K
Kansy
Janice W
JW
Hale
Carly F
CF
Moy
Lily Y
LY
Kim
Yong
Y
O'Callaghan
James P
JP
Tsai
Li-Huei
LH
Greengard
Paul
P
Nairn
Angus C
AC
Cowan
Christopher W
CW
Miller
Diane B
DB
Antich
Pietro
P
Bibb
James A
JA
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
D016194:Receptors, N-Methyl-D-Aspartate; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D003042:Cocaine