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Understanding and manipulating the dysregulation of interneurons in schizophrenia

Description du projet

Aperçu mécaniste du développement de la schizophrénie

La schizophrénie est une maladie mentale grave associée à une psychose et à une perception déformée de la réalité. Bien que les patients présentent une augmentation des niveaux de dopamine avant la psychose et une activité anormale présumée des neurones dopaminergiques du mésencéphale, le mécanisme précis reste insaisissable. Le projet SchizoFree, financé par l’UE, vise à faire la lumière sur l’étiologie du dérèglement des neurones dopaminergiques dans la schizophrénie. À l’aide d’un modèle murin de la maladie, les chercheurs étudieront le rôle des interneurones corticaux et striataux dans le développement de la schizophrénie. Ils espèrent identifier des biomarqueurs pour un diagnostic rapide de la maladie et concevoir de nouveaux traitements qui atténuent les symptômes de la schizophrénie.

Objectif

Schizophrenia is an incurable disease hallmarked by the presence of positive, negative and cognitive symptoms. Currently, antipsychotic drugs are used to treat some of the positive symptoms, including psychosis but fail to alleviate cognitive and negative symptoms. Psychosis is associated with striatal hyperdopaminergia, hypothesized to be due to abnormal activity of midbrain dopamine neurons. Dopamine levels are already elevated in patients with schizophrenia before the onset of psychosis, suggesting that increased dopamine levels might be secondary to other alterations occurring earlier in life. Additionally, functional alterations in the prefrontal cortex contribute to the disease, and interestingly abnormally increased activity in cortical excitatory neurons leads to striatal hyperdopaminergia in mice. However, the mechanisms and developmental trajectory underlying schizophrenia is still unclear, challenging the development of novel treatment strategies. Previous work from the Marin and Rico labs has shown that reducing excitatory synapses received by Parvalbumin (PV)-expressing interneurons through deletion of tyrosine kinase receptor ErbB4 from these neurons causes a schizophrenia-like phenotype and striatal hyperdopaminergia. The first aim of this fellowship is to use this mouse model and answer the question whether striatal hyperdopaminergia is caused by interneuron dysregulation in the cortex and/or striatum. The second aim is to identify the mechanisms causing the abnormal regulation of striatal dopamine neurons and to characterize a developmental trajectory of the disease. In the third aim, I attempt to normalize interneuron function to alleviate a wider spectrum of schizophrenia symptoms, including symptoms in the cognitive and negative domain. This is important because it would allow a better treatment outcome and the identification of biomarkers for earlier detection of patients at risk.

Coordinateur

KING'S COLLEGE LONDON
Contribution nette de l'UE
€ 212 933,76
Adresse
STRAND
WC2R 2LS London
Royaume-Uni

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Région
London Inner London — West Westminster
Type d’activité
Higher or Secondary Education Establishments
Liens
Coût total
€ 212 933,76