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5‐HT6 receptor recruitment of mTOR as a mechanism for perturbed cognition in schizophrenia

Julie Meffre, Séverine Chaumont‐Dubel, Clotilde Mannoury la Cour, Florence Loiseau, David J. G. Watson, Anne Dekeyne, Martial Séveno, Jean‐Michel Rivet, Florence Gaven, Paul Déléris, Denis Hervé, Kevin C. F. Fone, Joël Bockaert, Mark J. Millan, Philippe Marin

Author Affiliations

  1. Julie Meffre1,2,3,
  2. Séverine Chaumont‐Dubel1,2,3,
  3. Clotilde Mannoury la Cour4,
  4. Florence Loiseau4,
  5. David J. G. Watson5,
  6. Anne Dekeyne4,
  7. Martial Séveno1,2,3,
  8. Jean‐Michel Rivet4,
  9. Florence Gaven1,2,3,
  10. Paul Déléris1,2,3,
  11. Denis Hervé6,
  12. Kevin C. F. Fone5,
  13. Joël Bockaert1,2,3,
  14. Mark J. Millan (mark.millan{at}fr.netgrs.com) *,4 and
  15. Philippe Marin (philippe.marin{at}igf.cnrs.fr) *,1,2,3
  1. 1CNRS, UMR‐5203, Institut de Génomique Fonctionnelle, Montpellier, France
  2. 2INSERM, U661, Montpellier, France
  3. 3Universités Montpellier 1 & 2, Montpellier, France
  4. 4Institut de Recherches Servier, Croissy‐sur‐Seine, France
  5. 5School of Biomedical Sciences, Medical School, Queen's Medical Centre, The University of Nottingham, Nottingham, UK
  6. 6Institut du Fer à Moulin, INSERM, UMRS‐839, UPMC, Paris, France
  1. * Mark J. Millan, Tel: +33 155 72 24 25; Fax: +33 155 72 20 82

    Philippe Marin, Tel: +33 434 35 92 13, Fax: +33 467 54 24 32

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Abstract

Cognitive deficits in schizophrenia severely compromise quality of life and are poorly controlled by current antipsychotics. While 5‐HT6 receptor blockade holds special promise, molecular substrates underlying their control of cognition remain unclear. Using a proteomic strategy, we show that 5‐HT6 receptors physically interact with several proteins of the mammalian target of rapamycin (mTOR) pathway, including mTOR. Further, 5‐HT6 receptor activation increased mTOR signalling in rodent prefrontal cortex (PFC). Linking this signalling event to cognitive impairment, the mTOR inhibitor rapamycin prevented deficits in social cognition and novel object discrimination induced by 5‐HT6 agonists. In two developmental models of schizophrenia, specifically neonatal phencyclidine treatment and post‐weaning isolation rearing, the activity of mTOR was enhanced in the PFC, and rapamycin, like 5‐HT6 antagonists, reversed these cognitive deficits. These observations suggest that recruitment of mTOR by prefrontal 5‐HT6 receptors contributes to the perturbed cognition in schizophrenia, offering new vistas for its therapeutic control.

  • Received March 26, 2012.
  • Revision received July 16, 2012.
  • Accepted July 31, 2012.
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This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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