Striatal Dysregulation of Cdk5 Alters Locomotor Responses to Cocaine, Motor Learning, and Dendritic Morphology

Details

• Personal Author:
  Antich P ; Benkovic SA ; Bibb JA ; Cowan CW ; Greengard P ; Hale CF ; Hayashi KJ ; Kansy JW ; Kim Y ; Meyer DA ; Miller DB ; Moy LY ; Nairn AC ; O'Callaghan JP ; Richer E ; Tsai LH
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Nervous System Nervous System Diseases Occupational Health Safety
• Keywords:
  Brain-function Drug-receptor Nerve-fibers Neurological-reactions Neurological-system Neuromotor-system Neuromotor-system-disorders Neurophysiological-effects Neurophysiology Neurotransmitters Substance-abuse

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• ISSN:
  0027-8424
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  Connecticut ; Georgia ; Massachusetts ; New York ; OSHA Region 1 ; OSHA Region 2 ; OSHA Region 4 ; OSHA Region 6 ; Texas
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  105
• Issue:
  47
• NIOSHTIC Number:
  nn:20034774
• Citation:
  Proc Natl Acad Sci U.S.A. 2008 Nov; 105(47):18561-18566
• Contact Point Address:
  James A. Bibb, Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390
• Email:
  james.bibbo@utsouthwestern.edu
• Federal Fiscal Year:
  2009
• NORA Priority Area:
  Services
• Peer Reviewed:
  True
• Source Full Name:
  Proceedings of the National Academy of Sciences of the United States of America.
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:95ab3e99073eb6043eb2735bbb0fecfef83c1fc57a436b9cc20416e0a20573114fad260b15530b077194b962dc902606ca1887546ae331a65e4d61091d4df194
• Download URL:
  https://stacks.cdc.gov/view/cdc/186861/cdc_186861_DS1.pdf
• File Type:
  [PDF - 1018.31 KB ]