Progressive divisions of multipotent neural progenitors generate late-born chandelier cells in the neocortex.

Diverse γ-aminobutyric acid (GABA)-ergic interneurons provide different modes of inhibition to support circuit operation in the neocortex. However, the cellular and molecular mechanisms underlying the systematic generation of assorted neocortical interneurons remain largely unclear. Here we show that NKX2.1-expressing radial glial progenitors (RGPs) in the mouse embryonic ventral telencephalon divide progressively to generate distinct groups of interneurons, which occupy the neocortex in a time-dependent, early inside-out and late outside-in, manner. Notably, the late-born chandelier cells, one of the morphologically and physiologically highly distinguishable GABAergic interneurons, arise reliably from continuously dividing RGPs that produce non-chandelier cells initially. Selective removal of Partition defective 3, an evolutionarily conserved cell polarity protein, impairs RGP asymmetric cell division, resulting in premature depletion of RGPs towards the late embryonic stages and a consequent loss of chandelier cells. These results suggest that consecutive asymmetric divisions of multipotent RGPs generate diverse neocortical interneurons in a progressive manner.

Generation of diverse cortical inhibitory interneurons.

First described by Ramon y Cajal as 'short-axon' cells over a century ago, inhibitory interneurons in the cerebral cortex make up ~20-30% of the neuronal milieu. A key feature of these interneurons is the striking structural and functional diversity, which allows them to modulate neural activity in diverse ways and ultimately endow neural circuits with remarkable computational power. Here, we review our current understanding of the generation of cortical interneurons, with a focus on recent efforts to bridge the gap between progenitor behavior and interneuron production, and how these aspects influence interneuron diversity and organization. WIREs Dev Biol 2018, 7:e306. doi: 10.1002/wdev.306 This article is categorized under: Nervous System Development > Vertebrates: General Principles.

Precise inhibitory microcircuit assembly of developmentally related neocortical interneurons in clusters.

GABA-ergic interneurons provide diverse inhibitions that are essential for the operation of neuronal circuits in the neocortex. However, the mechanisms that control the functional organization of neocortical interneurons remain largely unknown. Here we show that developmental origins influence fine-scale synapse formation and microcircuit assembly of neocortical interneurons. Spatially clustered neocortical interneurons originating from low-titre retrovirus-infected radial glial progenitors in the embryonic medial ganglionic eminence and preoptic area preferentially develop electrical, but not chemical, synapses with each other. This lineage-related electrical coupling forms predominantly between the same interneuron subtype over an extended postnatal period and across a range of distances, and promotes action potential generation and synchronous firing. Interestingly, this selective electrical coupling relates to a coordinated inhibitory chemical synapse formation between sparsely labelled interneurons in clusters and the same nearby excitatory neurons. These results suggest a link between the lineage relationship of neocortical interneurons and their precise functional organization.

Clonally Related GABAergic Interneurons Do Not Randomly Disperse but Frequently Form Local Clusters in the Forebrain.

Progenitor cells in the medial ganglionic eminence (MGE) and preoptic area (PoA) give rise to GABAergic inhibitory interneurons that are distributed in the forebrain, largely in the cortex, hippocampus, and striatum. Two previous studies suggest that clonally related interneurons originating from individual MGE/PoA progenitors frequently form local clusters in the cortex. However, Mayer et al. and Harwell et al. recently argued that MGE/PoA-derived interneuron clones disperse widely and populate different forebrain structures. Here, we report further analysis of the spatial distribution of clonally related interneurons and demonstrate that interneuron clones do not non-specifically disperse in the forebrain. Around 70% of clones are restricted to one brain structure, predominantly the cortex. Moreover, the regional distribution of clonally related interneurons exhibits a clear clustering feature, which cannot occur by chance from a random diffusion. These results confirm that lineage relationship influences the spatial distribution of inhibitory interneurons in the forebrain. This Matters Arising paper is in response to Harwell et al. (2015) and Mayer et al. (2015), published in Neuron. See also the response by Turrero García et al. (2016) and Mayer et al. (2016), published in this issue.

Clonal origins of neocortical interneurons.

Once referred to as 'short-axon' neurons by Cajal, GABA (gamma-amino butyric acid)-ergic interneurons are essential components of the neocortex. They are distributed throughout the cortical laminae and are responsible for shaping circuit output through a rich array of inhibitory mechanisms. Numerous fate-mapping and transplantation studies have examined the embryonic origins of the diversity of interneurons that are defined along various parameters such as morphology, neurochemical marker expression and physiological properties, and have been extensively reviewed elsewhere. Here, we focus on discussing two recent studies that have, for the first time, examined the production and organization of neocortical interneurons originated from individual progenitors, that is, with clonal resolution, and provided important new insights into the cellular processes underlying the development of inhibitory interneurons in the neocortex.

Production and organization of neocortical interneurons.

Inhibitory GABA (γ-aminobutyric acid)-ergic interneurons are a vital component of the neocortex responsible for shaping its output through a variety of inhibitions. Consisting of many flavors, interneuron subtypes are predominantly defined by their morphological, physiological, and neurochemical properties that help to determine their functional role within the neocortex. During development, these cells are born in the subpallium where they then tangentially migrate over long distances before being radially positioned to their final location in the cortical laminae. As development progresses into adolescence, these cells mature and form chemical and electrical connections with both glutamatergic excitatory neurons and other interneurons ultimately establishing the cortical network. The production, migration, and organization of these cells are determined by vast array of extrinsic and intrinsic factors that work in concert in order to assemble a proper functioning cortical inhibitory network. Failure of these cells to undergo these processes results in abnormal positioning and cortical function. In humans, this can bring about several neurological disorders including schizophrenia, epilepsy, and autism spectrum disorders. In this article, we will review previous literature that has revealed the framework for interneuron neurogenesis and migratory behavior as well as discuss recent findings that aim to elucidate the spatial and functional organization of interneurons within the neocortex.

Lineage-dependent circuit assembly in the neocortex.

The neocortex plays a key role in higher-order brain functions, such as perception, language and decision-making. Since the groundbreaking work of Ramón y Cajal over a century ago, defining the neural circuits underlying brain functions has been a field of intense study. Here, we review recent findings on the formation of neocortical circuits, which have taken advantage of improvements to mouse genetics and circuit-mapping tools. These findings are beginning to reveal how individual components of circuits are generated and assembled during development, and how early developmental processes, such as neurogenesis and neuronal migration, guide precise circuit assembly.