Neurobiology of Schizophrenia

The last two decades have seen a revolution in the development of molecular and cellular neurobiology and improvement of neuroimaging methods. Large-scale genome-wide association studies have identified about 270 candidate risk genes for schizophrenia that are related to neuronal excitability, development, and structure, with prominent enrichments at the synapse. Neuroimaging studies point to structural abnormalities in frontotemporal regions, deficits in fiber density and myelination, and a reduction in functional connectivity networks, all of which may underlie neurocognitive deficits. In early phases of the illness, structural deficits and functional dysconnectivity are involved in conversion from high-risk states to full-blown/manifest schizophrenia. For the first time, aerobic exercise studies support the notion that the regenerative capacities of the brain can be stimulated in patients with multi-episode schizophrenia. Post-mortem findings show not only deficits in neuronal and energy metabolism but also decreases in oligodendrocytes in general and in proteins in specific brain regions. Human-induced pluripotent stem cells (hiPSCs) represent an in vivo model system that will facilitate the future study of the influence of genetic architecture; first studies in small cohorts report deficits in cellular differentiation and function. In summary, schizophrenia is a complex brain disorder where genetic and environmental risk factors interact. Novel tools such as hiPSCs and animal models of risk factors and large-scale molecular and neuroimaging studies are enabling the investigation of the neurobiological riddle of schizophrenia and its prodromes. Confirming key mechanisms would provide a basis for the development of innovative treatment strategies.