Cortical Circuit Development: Intrinsic and Extrinsic Factors Underlying the Connectivity of Inhibitory Neurons

Abstract

The cerebral cortex is a brain structure that is involved in a variety of complex tasks, such as language, learning and reasoning. Many different cell types are involved in the execution of these tasks, including excitatory neurons and inhibitory neurons. Communication between these neuron types is important, because inhibitory neurons regulate the activity of the excitatory neurons. However, the excitatory neurons and inhibitory neurons are not born at the same place. While excitatory neurons will reside in locations close to the regions where they were born, the inhibitory neurons are required to move in order to be able to communicate with excitatory neurons. The processes of inhibitory neuron generation, migration and the formation of connections is strictly regulated during different developmental stages. The inhibitory neurons are generated in a transient embryonic region below the cortex. At different locations within this region, different concentrations of proteins are present. These proteins influence the type of inhibitory neuron is generated. Furthermore, interneurons can also receive some information from their progenitors to become a specific type of interneuron. With maturation, inhibitory neurons also become responsive to signals that can either attract them or repel them from the cerebral cortex. The cerebral cortex consists of six layers formed by excitatory neurons. Upon arrival in the cortex, the inhibitory neurons undergo a second phase of migration, in which the different kinds of inhibitory neurons populate specific layers of the cortex. Usually, too many inhibitory neurons reach their final destination. During brain development, a fraction of the inhibitory neurons will be instructed to undergo cell death. The remaining inhibitory neurons form connections with excitatory neurons. In this way, a network of excitatory and inhibitory neurons is formed. While making connections with excitatory neurons, the inhibitory neurons also acquire the properties that are necessary for their functions in the cerebral cortex in adulthood. Disruptions in any of the steps involved in bringing inhibitory neurons to the cerebral cortex could result in disorders such as autism or schizophrenia. Therefore, it is important to understand which mechanisms are involved in the regulation of each developmental step. In this review, I provide an overview on which factors are involved in the generation of inhibitory neurons, migration and integration in cortical layers. Thereby, I hope to advance our understanding of the origin and the development of the networks in the cerebral cortex and to contribute to our knowledge of several neurodevelopmental disorders.