Die Rolle des Gens Disrupted-in-Schizophrenia-1 (DISC1) während der tangentialen Migration kortikaler Interneurone der Maus
The gene “Disrupted-in-Schizophrenia-1” (DISC1) got into the scientific focus of Psychiatrists and Neurobiologists at the beginning of the century. A disruption of this gene was discovered within members of a Scottish family, who have a higher predisposition to develop schizophrenia spectrum disorders (Chubb et al., 2008). The DISC1 gene encodes a protein, which showed multiple functions in neuronal cells, e.g. during proliferation, migration and positioning of neurons or the development of synapses. In this doctoral thesis the role of DISC1 during neuronal migration, especially interneuron migration was examined. These cells make up around 20% of all cortical neurons, thus representing a minority of neurons in the cortex. However, they are highly diverse in morphological as well as functional aspects and are necessary for the correct balance between excitation and inhibition in the brain. Thus it has been described, that patients with epilepsy, autism or schizophrenia display deficits in cortical interneurons. (Le Magueresse and Monyer, 2013) In the present study it has been shown, that DISC1 is necessary for the correct tangential migration of interneurons in mice. The gene is expressed at embryonic stage E14.5 in precursor cells of parvalbuminergic interneurons deriving from the MGE. Using RNA interference techniques it was possible to successfully down regulate the DISC1 expression in those neurons, thereafter they react with a reduced migratory behavior. The dynamic observation of DISC1-deficient interneurons showed that the complex process of the saltatory movement of these cells was disturbed. This process is realized by cytoskeletal components and it was found that the reorganization of the actin cytoskeleton in DISC1-deficient interneurons was incorrect. In addition to the migration defect examined in vitro, this scenario could be reproduced in vivo using in utero electroporation to transfect MGE-derived interneurons with DISC1 or control miRNA. These experiments showed that fewer cells reached the cortex if they were transfected with DISC1-miRNA compared to the transfection with control constructs. These findings provide a possible link between clinical studies reporting alterations of cortical interneurons in schizophrenic patients and the current notion of schizophrenia as a neurodevelopmental disorder (Lewis and Levitt, 2002).