Any neuronal differentiation process consists of an initial neural induction of hiPSCs, mediated by appropriate concentrations and gradients of several morphogenetic factors that are normally expressed in the developing brain. In the case of autism, schizophrenia, intellectual disabilities, and in many other disorders primarily affecting higher cognitive functions, several in vitro protocols have been developed with the ultimate goal of mimicking the development of the cerebral cortex. The mature cerebral cortex is a six-layered structure composed of two main classes of neurons: glutamatergic excitatory neurons and GABAergic inhibitory interneurons. Moreover, different subtypes of neurons are located in different cortical layers. The fate specification and differentiation of the different subtypes of cortical neurons is determined by the expression of specific combinations of transcription factors in each subpopulation, responsible for their functional diversity. The hiPSC neuronal differentiation strategy should be chosen to mimic the differentiation process with the aim of understanding its derailment in developmental disorders.
