The suppression of brain cold-stable microtubules in mice induces synaptic defects associated with neuroleptic-sensitive behavioral disorders

  1. Annie Andrieux1,
  2. Paul A. Salin3,
  3. Muriel Vernet2,
  4. Pekka Kujala4,
  5. Julie Baratier1,
  6. Sylvie Gory-Fauré1,
  7. Christophe Bosc1,
  8. Hervé Pointu2,
  9. Dominique Proietto1,
  10. Annie Schweitzer1,
  11. Eric Denarier1,
  12. Judith Klumperman4, and
  13. Didier Job1,5
  1. 1Laboratoire du Cytosquelette, INSERM U366; 2Atelier de Transgenèse, Département Réponse et Dynamique Cellulaire, CEA-Grenoble, 38054 Grenoble, France; 3Centre Européen des Sciences du Goût, CNRS, 21000 Dijon, France; 4Department of Cell Biology, Institute of Biomembranes, University Medical Centre Utrecht, 3584 CX Utrecht, The Netherlands

Abstract

Neurons contain abundant subsets of highly stable microtubules that resist depolymerizing conditions such as exposure to the cold. Stable microtubules are thought to be essential for neuronal development, maintenance, and function. Previous work has indicated an important role of the microtubule-associated protein STOP in the induction of microtubule cold stability. Here, we developed STOP null mice. These mice were devoid of cold-stable microtubules. In contrast to our expectations, STOP−/− mice had no detectable defects in brain anatomy but showed synaptic defects, with depleted synaptic vesicle pools and impaired synaptic plasticity, associated with severe behavioral disorders. A survey of the effects of psychotropic drugs on STOP−/− mice behavior showed a remarkable and specific effect of long-term administration of neuroleptics in alleviating these disorders. This study demonstrates that STOP is a major factor responsible for the intriguing stability properties of neuronal microtubules and is important for synaptic plasticity. Additionally, STOP−/− mice may yield a pertinent model for study of neuroleptics in illnesses such as schizophrenia, currently thought to result from synaptic defects.

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Footnotes

  • 5 Corresponding author.

  • E-MAIL djob{at}cea.fr; FAX 33-43-878-5057.

  • Article and Publication are at httP://www.genesdev.org/cgi/doi/10.1101/gad.223302.

    • Received December 17, 2001.
    • Accepted July 9, 2002.
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