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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.

Pubmed ID: 19017804


  • Meyer DA
  • Richer E
  • Benkovic SA
  • Hayashi K
  • Kansy JW
  • Hale CF
  • Moy LY
  • Kim Y
  • O'Callaghan JP
  • Tsai LH
  • Greengard P
  • Nairn AC
  • Cowan CW
  • Miller DB
  • Antich P
  • Bibb JA


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

November 25, 2008

Associated Grants

  • Agency: NIDA NIH HHS, Id: DA10044
  • Agency: NIDA NIH HHS, Id: DA16672
  • Agency: NHLBI NIH HHS, Id: HL077101
  • Agency: NIMH NIH HHS, Id: MH074866
  • Agency: NIMH NIH HHS, Id: MH079710-0
  • Agency: NINDS NIH HHS, Id: NS051874
  • Agency: NIDA NIH HHS, Id: P01 DA010044
  • Agency: NIDA NIH HHS, Id: T32-DA7290
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • Behavior, Animal
  • Cocaine
  • Corpus Striatum
  • Cyclin-Dependent Kinase 5
  • Dendrites
  • Learning
  • Locomotion
  • Mice
  • Mice, Transgenic
  • Receptors, N-Methyl-D-Aspartate