[Bridging the genomic approach and the neurodevelopmental and neurodenerative hypothesis of schizophrenia]

Schizophrenia is hypothesized as a neurodevelopmental and neurodegenerative disorder based on the following findings. 1. MRI studies have revealed brain structural abnormalities from the onset of schizophrenia and the progress of these structural abnormalities. 2. Histopathological studies have elucidated cytoarchitectural abnormalities in schizophrenic brains without gliosis. 3. Obstetric complications are one of the risk factors for schizophrenia. 4. Relapse of schizophrenia results in a deteriorating progress of the disorder. Furthermore, data from family, twin and adoption studies show evidence of a substantial genetic component in schizophrenia, Thus, a molecular genetic study combined with a neurodevelopmental and neurodegenerative hypothesis is required to elucidate the pathophysiology of schizophrenia. The positive association between neuregulin 1 and Icelandic schizophrenia that has been reproduced in Scottish and North European schizophrenia is one of the intriguing examples of this type of research. Neuregulin 1 regulates the cytoarchitecture of brain. Mice mutated for neuregulin 1 show a behavioral phenotype that overlaps with mouse models for schizophrenia. Furthermore, the behavioral phenotypes of the neuregulin 1 hypomorphs are reversible with clozapine. We also demonstrated a positive association between schizophrenia and a 5-HT5A receptor polymorphism, Pro15Ser, that may have role in cell differentiation in the brain.