Understanding and manipulating the dysregulation of interneurons in schizophrenia

Descripción del proyecto

Conocimiento mecanicista del desarrollo de la esquizofrenia

La esquizofrenia es una enfermedad mental grave asociada con la psicosis y la percepción distorsionada de la realidad. Aunque los esquizofrénicos presentan niveles elevados de dopamina antes de la psicosis y se sospecha de una actividad anormal de las neuronas dopaminérgicas del mesencéfalo, aún se desconocen los mecanismos precisos. El proyecto SchizoFree, financiado con fondos europeos, tiene como objetivo proporcionar conocimientos nuevos sobre el origen de la desregulación de las neuronas dopaminérgicas en la esquizofrenia. Sus investigadores emplearán un modelo murino de la esquizofrenia para estudiar el papel de las interneuronas corticales y estriatales en el desarrollo de esta enfermedad. Esperan identificar biomarcadores para el diagnóstico rápido de la esquizofrenia y diseñar tratamientos novedosos que alivien sus síntomas.

Objetivo

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.