Understanding and manipulating the dysregulation of interneurons in schizophrenia

Descrizione del progetto

Intuizione meccanicistica nello sviluppo della schizofrenia

La schizofrenia è una grave malattia mentale associata a psicosi e percezione distorta della realtà. Sebbene i pazienti presentino maggiori livelli di dopamina prima della psicosi e una sospetta attività anomala dei neuroni dopaminergici del mesencefalo, i precisi meccanismi rimangono ancora ignoti. Il progetto SchizoFree, finanziato dall’UE, si propone di far luce sull’eziologia della disregolazione dei neuroni dopaminergici nella schizofrenia. Utilizzando un modello murino della malattia, alcuni ricercatori studieranno il ruolo degli interneuroni corticali e striatali nello sviluppo della schizofrenia. Essi sperano di identificare i biomarcatori per la diagnosi tempestiva della malattia e di progettare nuove cure in grado di alleviare i sintomi della schizofrenia.

Obiettivo

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.