Abstract
During evolution, the cerebral cortex advances by increasing in surface and the introduction of new cytoarchitectonic areas among which the prefrontal cortex (PFC) is considered to be the substrate of highest cognitive functions. Although neurons of the PFC are generated before birth, the differentiation of its neurons and development of synaptic connections in humans extend to the 3rd decade of life. During this period, synapses as well as neurotransmitter systems including their receptors and transporters, are initially overproduced followed by selective elimination. Advanced methods applied to human and animal models, enable investigation of the cellular mechanisms and role of specific genes, non-coding regulatory elements and signaling molecules in control of prefrontal neuronal production and phenotypic fate, as well as neuronal migration to establish layering of the PFC. Likewise, various genetic approaches in combination with functional assays and immunohistochemical and imaging methods reveal roles of neurotransmitter systems during maturation of the PFC. Disruption, or even a slight slowing of the rate of neuronal production, migration and synaptogenesis by genetic or environmental factors, can induce gross as well as subtle changes that eventually can lead to cognitive impairment. An understanding of the development and evolution of the PFC provide insight into the pathogenesis and treatment of congenital neuropsychiatric diseases as well as idiopathic developmental disorders that cause intellectual disabilities.