5‐HT6 receptor recruitment of mTOR as a mechanism for perturbed cognition in schizophrenia
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 th...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2012-10-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/emmm.201201410 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850179082193469440 |
|---|---|
| author | 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_facet | 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_sort | Julie Meffre |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-a0066cfd997d434495adbb9a5a7bd59e |
| institution | OA Journals |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2012-10-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-a0066cfd997d434495adbb9a5a7bd59e2025-08-20T02:18:35ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842012-10-014101043105610.1002/emmm.2012014105‐HT6 receptor recruitment of mTOR as a mechanism for perturbed cognition in schizophreniaJulie Meffre0Séverine Chaumont‐Dubel1Clotilde Mannoury la Cour2Florence Loiseau3David J. G. Watson4Anne Dekeyne5Martial Séveno6Jean‐Michel Rivet7Florence Gaven8Paul Déléris9Denis Hervé10Kevin C. F. Fone11Joël Bockaert12Mark J. Millan13Philippe Marin14CNRS, UMR‐5203, Institut de Génomique FonctionnelleCNRS, UMR‐5203, Institut de Génomique FonctionnelleInstitut de Recherches ServierInstitut de Recherches ServierSchool of Biomedical Sciences, Medical School, Queen's Medical Centre, The University of NottinghamInstitut de Recherches ServierCNRS, UMR‐5203, Institut de Génomique FonctionnelleInstitut de Recherches ServierCNRS, UMR‐5203, Institut de Génomique FonctionnelleCNRS, UMR‐5203, Institut de Génomique FonctionnelleInstitut du Fer à Moulin, INSERM, UMRS‐839, UPMCSchool of Biomedical Sciences, Medical School, Queen's Medical Centre, The University of NottinghamCNRS, UMR‐5203, Institut de Génomique FonctionnelleInstitut de Recherches ServierCNRS, UMR‐5203, Institut de Génomique FonctionnelleAbstract 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.https://doi.org/10.1002/emmm.2012014105‐HT6 receptorcognitionmTORC1proteomicsschizophrenia |
| spellingShingle | 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 5‐HT6 receptor recruitment of mTOR as a mechanism for perturbed cognition in schizophrenia EMBO Molecular Medicine 5‐HT6 receptor cognition mTORC1 proteomics schizophrenia |
| title | 5‐HT6 receptor recruitment of mTOR as a mechanism for perturbed cognition in schizophrenia |
| title_full | 5‐HT6 receptor recruitment of mTOR as a mechanism for perturbed cognition in schizophrenia |
| title_fullStr | 5‐HT6 receptor recruitment of mTOR as a mechanism for perturbed cognition in schizophrenia |
| title_full_unstemmed | 5‐HT6 receptor recruitment of mTOR as a mechanism for perturbed cognition in schizophrenia |
| title_short | 5‐HT6 receptor recruitment of mTOR as a mechanism for perturbed cognition in schizophrenia |
| title_sort | 5 ht6 receptor recruitment of mtor as a mechanism for perturbed cognition in schizophrenia |
| topic | 5‐HT6 receptor cognition mTORC1 proteomics schizophrenia |
| url | https://doi.org/10.1002/emmm.201201410 |
| work_keys_str_mv | AT juliemeffre 5ht6receptorrecruitmentofmtorasamechanismforperturbedcognitioninschizophrenia AT severinechaumontdubel 5ht6receptorrecruitmentofmtorasamechanismforperturbedcognitioninschizophrenia AT clotildemannourylacour 5ht6receptorrecruitmentofmtorasamechanismforperturbedcognitioninschizophrenia AT florenceloiseau 5ht6receptorrecruitmentofmtorasamechanismforperturbedcognitioninschizophrenia AT davidjgwatson 5ht6receptorrecruitmentofmtorasamechanismforperturbedcognitioninschizophrenia AT annedekeyne 5ht6receptorrecruitmentofmtorasamechanismforperturbedcognitioninschizophrenia AT martialseveno 5ht6receptorrecruitmentofmtorasamechanismforperturbedcognitioninschizophrenia AT jeanmichelrivet 5ht6receptorrecruitmentofmtorasamechanismforperturbedcognitioninschizophrenia AT florencegaven 5ht6receptorrecruitmentofmtorasamechanismforperturbedcognitioninschizophrenia AT pauldeleris 5ht6receptorrecruitmentofmtorasamechanismforperturbedcognitioninschizophrenia AT denisherve 5ht6receptorrecruitmentofmtorasamechanismforperturbedcognitioninschizophrenia AT kevincffone 5ht6receptorrecruitmentofmtorasamechanismforperturbedcognitioninschizophrenia AT joelbockaert 5ht6receptorrecruitmentofmtorasamechanismforperturbedcognitioninschizophrenia AT markjmillan 5ht6receptorrecruitmentofmtorasamechanismforperturbedcognitioninschizophrenia AT philippemarin 5ht6receptorrecruitmentofmtorasamechanismforperturbedcognitioninschizophrenia |