Abstract
Since more than 3 decades, schizophrenia (SZ) has been regarded as a neurodevelopmental disorder. The neurodevelopmental hypothesis proposes that SZ is associated with genetic and environmental risk factors, which influence connectivity in neuronal circuits during vulnerable developmental periods. We carried out a non-systematic review of genetic/environmental factors that increase SZ risk in light of its neurodevelopmental hypothesis. We also reviewed the potential impact of SZ-related environmental and genetic risk factors on grey and white matter pathology and brain function based on magnetic resonance imaging and post-mortem studies. Finally, we reviewed studies that have used patient-derived neuronal models to gain knowledge of the role of genetic and environmental factors in early developmental stages. Taken together, these studies indicate that a variety of environmental factors may interact with genetic risk factors during the pre- or postnatal period and/or during adolescence to induce symptoms of SZ in early adulthood. These risk factors induce disturbances of macro- and microconnectivity in brain regions involving the prefrontal, temporal and parietal cortices and the hippocampus. On the molecular and cellular level, a disturbed synaptic plasticity, loss of oligodendrocytes and impaired myelination have been shown in brain regions of SZ patients. These cellular/histological phenotypes are related to environmental risk factors such as obstetric complications, maternal infections and childhood trauma and genetic risk factors identified in recent genome-wide association studies. SZ-related genetic risk may contribute to active processes interfering with synaptic plasticity in the adult brain. Advances in stem cell technologies are providing promising mechanistic insights into how SZ risk factors impact the developing brain. Further research is needed to understand the timing of the different complex biological processes taking place as a result of the interplay between genetic and environmental factors.