In the cerebral cortex, GABAergic interneurons have evolved as a highly heterogeneous collection of cell types that are characterized by their unique spatial and temporal capabilities to influence neuronal circuits. Current estimates suggest that up to 50 different types of GABAergic neurons may populate the cerebral cortex, all derived from progenitor cells in the subpallium, the ventral aspect of the embryonic telencephalon. In this review, we provide an overview of the mechanisms underlying the generation of the distinct types of interneuron and their integration in cortical circuits. Interneuron diversity seems to emerge through the implementation of cell-intrinsic genetic programs in progenitor cells, which unfold over a protracted period of time until interneurons acquire mature characteristics. The developmental trajectory of interneurons is also modulated by activity-dependent, non-cell autonomous mechanisms that influence their ability to integrate in nascent circuits and sculpt their final distribution in the adult cerebral cortex.

The cerebral cortex contains multiple areas with distinctive cytoarchitectonic patterns, but the cellular mechanisms underlying the emergence of this diversity remain unclear. Here, we have investigated the neuronal output of individual progenitor cells in the developing mouse neocortex using a combination of methods that together circumvent the biases and limitations of individual approaches. Our experimental results indicate that progenitor cells generate pyramidal cell lineages with a wide range of sizes and laminar configurations. Mathematical modeling indicates that these outcomes are compatible with a stochastic model of cortical neurogenesis in which progenitor cells undergo a series of probabilistic decisions that lead to the specification of very heterogeneous progenies. Our findings support a mechanism for cortical neurogenesis whose flexibility would make it capable to generate the diverse cytoarchitectures that characterize distinct neocortical areas.

Neural circuit assembly relies on the precise synchronization of developmental processes, such as cell migration and axon targeting, but the cell-autonomous mechanisms coordinating these events remain largely unknown. Here we found that different classes of interneurons use distinct routes of migration to reach the embryonic cerebral cortex. Somatostatin-expressing interneurons that migrate through the marginal zone develop into Martinotti cells, one of the most distinctive classes of cortical interneurons. For these cells, migration through the marginal zone is linked to the development of their characteristic layer 1 axonal arborization. Altering the normal migratory route of Martinotti cells by conditional deletion of Mafb-a gene that is preferentially expressed by these cells-cell-autonomously disrupts axonal development and impairs the function of these cells in vivo. Our results suggest that migration and axon targeting programs are coupled to optimize the assembly of inhibitory circuits in the cerebral cortex.

The mammalian cerebral cortex represents one of the most recent and astonishing inventions of nature, responsible of a large diversity of functions that range from sensory processing to high-order cognitive abilities, such as logical reasoning or language. Decades of dedicated study have contributed to our current understanding of this structure, both at structural and functional levels. A key feature of the neocortex is its outstanding richness in cell diversity, composed by multiple types of long-range projecting neurons and locally connecting interneurons. In this review, we will describe the great diversity of interneurons that constitute local neocortical circuits and summarize the mechanisms underlying their development and their assembly into functional networks.

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