Variations in Dysbindin-1 are associated with cognitive response to antipsychotic drug treatment.

Détails

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Etat: Public
Version: Final published version
ID Serval
serval:BIB_0BD8D7D05BDD
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Variations in Dysbindin-1 are associated with cognitive response to antipsychotic drug treatment.
Périodique
Nature communications
Auteur⸱e⸱s
Scheggia D., Mastrogiacomo R., Mereu M., Sannino S., Straub R.E., Armando M., Managò F., Guadagna S., Piras F., Zhang F., Kleinman J.E., Hyde T.M., Kaalund S.S., Pontillo M., Orso G., Caltagirone C., Borrelli E., De Luca M.A., Vicari S., Weinberger D.R., Spalletta G., Papaleo F.
ISSN
2041-1723 (Electronic)
ISSN-L
2041-1723
Statut éditorial
Publié
Date de publication
11/06/2018
Peer-reviewed
Oui
Volume
9
Numéro
1
Pages
2265
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Résumé
Antipsychotics are the most widely used medications for the treatment of schizophrenia spectrum disorders. While such drugs generally ameliorate positive symptoms, clinical responses are highly variable in terms of negative symptoms and cognitive impairments. However, predictors of individual responses have been elusive. Here, we report a pharmacogenetic interaction related to a core cognitive dysfunction in patients with schizophrenia. We show that genetic variations reducing dysbindin-1 expression can identify individuals whose executive functions respond better to antipsychotic drugs, both in humans and in mice. Multilevel ex vivo and in vivo analyses in postmortem human brains and genetically modified mice demonstrate that such interaction between antipsychotics and dysbindin-1 is mediated by an imbalance between the short and long isoforms of dopamine D2 receptors, leading to enhanced presynaptic D2 function within the prefrontal cortex. These findings reveal one of the pharmacodynamic mechanisms underlying individual cognitive response to treatment in patients with schizophrenia, suggesting a potential approach for improving the use of antipsychotic drugs.
Mots-clé
Adolescent, Adult, Aged, Animals, Antipsychotic Agents/pharmacology, Brain/drug effects, Brain/metabolism, Cognition/drug effects, Cognition/physiology, Dysbindin/deficiency, Dysbindin/genetics, Dysbindin/metabolism, Executive Function/drug effects, Executive Function/physiology, Genetic Variation, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Prefrontal Cortex/drug effects, Prefrontal Cortex/metabolism, Receptors, Dopamine D2/metabolism, Risperidone/pharmacology, Schizophrenia/drug therapy, Schizophrenia/genetics, Schizophrenia/metabolism, Schizophrenic Psychology, Young Adult
Pubmed
Web of science
Open Access
Oui
Création de la notice
25/06/2018 9:00
Dernière modification de la notice
21/11/2022 8:27
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