Cortical development and neuropathology in schizophrenia

Epidemiological studies suggest that perturbations occurring during pregnancy can increase the incidence of schizophrenia among offspring. Examination of the neuropathology of the brains of some schizophrenics suggests that a defect in the later phases of cerebral cortical development, notably the last phases of neuronal migration and the establishment and refinement of patterns of cortical connections, may be involved. Most of these studies are conjectural, and the relationship between primary lesions and potential secondary retrograde and anterograde effects in the circuitry linking the prefrontal cortex, basal forebrain, mediodorsal thalamus and medial temporal cortex is unknown. Our hypothesis, based on neuromorphological and gene expression studies, is that a disturbance of migration or in the pattern of preprogrammed cell death in the subplate zone of the developing cerebral cortex causes a failure to establish normal patterns of connections in the overlying cortex. This compromised circuitry subsequently decompensates, leading to schizophrenic symptoms and activity-dependent manifestations of altered gene expression for neurotransmitter- and receptor-related molecules.