Loss of dendrite stabilization by the Abl-related gene (Arg) kinase regulates behavioral flexibility and sensitivity to cocaine.

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  • Author(s): Gourley SL;Gourley SL; Koleske AJ; Taylor JR
  • Source:
    Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2009 Sep 29; Vol. 106 (39), pp. 16859-64. Date of Electronic Publication: 2009 Sep 11.
  • Publication Type:
    Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : National Academy of Sciences
    • Subject Terms:
      Cocaine/*pharmacology ; Dendrites/*drug effects ; Dendrites/*physiology ; Dopamine Uptake Inhibitors/*pharmacology ; Protein-Tyrosine Kinases/*genetics ; Protein-Tyrosine Kinases/*metabolism; Animals ; Behavior, Animal/drug effects ; Cocaine/administration & dosage ; Disks Large Homolog 4 Protein ; Dopamine Uptake Inhibitors/administration & dosage ; Guanylate Kinases ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mice ; Mice, Knockout ; Mice, Transgenic ; Models, Animal
    • Abstract:
      Adolescence is characterized by increased vulnerability to developing neuropsychiatric disorders and involves a period of prefrontal cortical dendritic refinement and synaptic pruning that culminates in cytoskeletal stabilization in adulthood. The Abl-related gene (Arg) acts through p190RhoGAP to inhibit the RhoA GTPase and stabilize cortical dendritic arbors beginning in adolescence. Cortical axons, dendrites, and synapses develop normally in Arg-deficient (arg(-/-)) mice, but adult dendrites destabilize and regress; thus, arg(-/-) mice present a model of adolescent-onset dendritic simplification. We show that arg(-/-) mice are impaired in a reversal task and that deficits are grossly exacerbated by low-dose cocaine administration. Although ventral prefrontal dopamine D2 receptor levels predict "perseverative" error counts in wild-type mice, no such relationship is found in arg(-/-) mice. Moreover, arg(-/-) mice are insensitive to the disruptive effects of the D2/D3 antagonist haloperidol in reversal but show normal sensitivity to its locomotor-depressant actions. Arg deficiency and orbitofrontal cortical Arg inhibition via STI-571 infusion also enhance the psychomotor stimulant actions of cocaine. These findings provide evidence that stabilization of dendritic structure beginning in adolescence is critical for the development of adaptive and flexible behavior after cocaine exposure.
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    • Grant Information:
      F31 MH079680 United States MH NIMH NIH HHS; R01 NS039475 United States NS NINDS NIH HHS; RL1 AA017537 United States AA NIAAA NIH HHS; AA 017537 United States AA NIAAA NIH HHS; MH 079680 United States MH NIMH NIH HHS; DA 011717 United States DA NIDA NIH HHS; R01 DA011717 United States DA NIDA NIH HHS; UL1-DE19586 United States DE NIDCR NIH HHS; P20 DA027844 United States DA NIDA NIH HHS; R01 DA015222 United States DA NIDA NIH HHS; NS 039475 United States NS NINDS NIH HHS; UL1 DE019586 United States DE NIDCR NIH HHS
    • Accession Number:
      0 (Disks Large Homolog 4 Protein)
      0 (Dlg4 protein, mouse)
      0 (Dopamine Uptake Inhibitors)
      0 (Intracellular Signaling Peptides and Proteins)
      0 (Membrane Proteins)
      EC 2.7.1.- (ARG tyrosine kinase)
      EC 2.7.10.1 (Protein-Tyrosine Kinases)
      EC 2.7.4.8 (Guanylate Kinases)
      I5Y540LHVR (Cocaine)
    • Publication Date:
      Date Created: 20091007 Date Completed: 20091228 Latest Revision: 20220309
    • Publication Date:
      20231215
    • Accession Number:
      PMC2742404
    • Accession Number:
      10.1073/pnas.0902286106
    • Accession Number:
      19805386