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Understanding and manipulating the dysregulation of interneurons in schizophrenia

Project description

Mechanistic insight into schizophrenia development

Schizophrenia is a serious mental illness associated with psychosis and distorted perception of reality. Although patients present with increased dopamine levels before psychosis and suspected abnormal activity of midbrain dopamine neurons, the precise mechanisms remain elusive. The EU-funded SchizoFree project aims to shed light on the aetiology of dopamine neuron dysregulation in schizophrenia. Using a mouse model of the disease, researchers will investigate the role of cortical and striatal interneurons in the development of schizophrenia. They hope to identify biomarkers for prompt disease diagnosis and design novel treatments that alleviate schizophrenia symptoms.

Objective

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.

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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)

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Call for proposal

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(opens in new window) H2020-MSCA-IF-2020

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Coordinator

KING'S COLLEGE LONDON
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 212 933,76
Address
STRAND
WC2R 2LS London
United Kingdom

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Region
London Inner London — West Westminster
Activity type
Higher or Secondary Education Establishments
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 212 933,76
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