Understanding and manipulating the dysregulation of interneurons in schizophrenia

Projektbeschreibung

Mechanistische Einblicke in die Entwicklung von Schizophrenie

Schizophrenie ist eine schwere psychische Erkrankung, die mit Psychosen und einer verzerrten Wahrnehmung der Wirklichkeit einhergeht. Obwohl die Betroffenen vor der Psychose einen erhöhten Dopaminspiegel aufweisen und eine abnorme Aktivität der Dopamin-Neuronen im Mittelhirn vermutet wird, ist der genaue Mechanismus immer noch ungeklärt. Das EU-finanzierte Projekt SchizoFree soll Aufschluss über die Ätiologie der neuronalen Dopamin-Dysregulation bei Schizophrenie geben. Anhand eines Mausmodells der Krankheit wird das Forschungsteam die Rolle der kortikalen und striatalen Interneuronen bei der Entstehung von Schizophrenie untersuchen. Die Hoffnung lautet, Biomarker für eine zügige Krankheitsdiagnose zu finden sowie neuartige Behandlungen zur Linderung der Schizophreniesymptome zu entwickeln.

Ziel

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.