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WIREs Dev Biol
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Generation of diverse cortical inhibitory interneurons

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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

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  • Nervous System Development > Vertebrates: General Principles
Multiple dimensions of cortical interneuron diversity. (a) Morphologically defined subtypes of interneurons. Black and colored lines represent dendritic and axonal processes, respectively. (b) Classification of subtypes based on molecular marker expression. PV, parvalbumin; SOM, somatostatin; VIP, vasointestinal peptide; CR, calretinin; CCK, cholecystokinin; NPY, neuropeptide Y; 5HTR‐3A, serotonin receptor 3A. (c) Electrophysiological classification of interneurons based on the action potential response pattern upon electrical stimulation. FS, fast‐spiking; LS, late‐spiking; IS, irregular‐spiking; LTS, low threshold spiking; BST, bursting. (d) Diversity in subcellular targeting. (e) Diversity in cellular targeting. E, excitatory neuron. (f) Patterns of electrical synapse formation in different interneuron subtypes. (g) Morphologically defined subtypes that are particularly numerous and refined in primates.
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Lineage‐related production, organization and functional development of cortical interneurons. (a) Radial glial progenitors (RGPs) at the ventricular surface of the medial ganglionic eminence (MGE) and preoptic area (PoA) undergo asymmetric divisions (A.D.) to self‐renew and simultaneously generate a postmitotic interneuron (IN) or an intermediate progenitor cell (IPC), which can further undergo symmetric divisions (S.D.) in the subventricular zone to produce differentiating interneurons. In the mature cortex, clonally related interneurons do not randomly disperse, but are frequently organized in spatially isolated intra‐ or interlaminar clusters. LGE, lateral ganglionic eminence; Ctx, cortex. (b) Clonally labeled interneurons in clusters (green) preferentially form electrical, but not chemical, synapses with each other compared to nearby, nonclonally related interneurons (red). This lineage‐related preferential electrical coupling promotes the coordinated formation of inhibitory synapses between clonally labeled interneurons and the same nearby excitatory cells in the cortex.
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Two models of generating diversity from radial glial progenitors (RGPs). A rich variety of neuronal subtypes can arise from either temporal fate restriction of a common pool of dividing RGPs (radial glial progenitors, Model 1) or via multiple distinct pools of fate‐restricted RGPs that are spatially segregated or enter mitosis at different times during embryonic neurogenesis (Model 2). The changes in neuronal progeny density may arise from the depletion of RGPs (dotted line). IPC, intermediate progenitor cell; L, layer; MGE, medial ganglionic eminence; PoA, preoptic area; IPC, intermediate progenitor cell.
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Spatial and temporal origins of MGE (medial ganglionic eminence)‐derived interneurons. (a) Spatial bias of progenitors to generate somatostatin (SOM)‐ and parvalbumin (PV)‐expressing cells in the dorsal and ventral regions of the MGE, respectively. SOM/calretinin (CR)‐expressing cells have been suggested to originate in the dorsal‐most tip of the MGE, where as chandelier cells (ChCs) are enriched in ventral MGE. LGE, lateral ganglionic eminence; PoA, preoptic area; Ctx, cortex, MC, Martinotti cells. (b) Temporal bias in MGE fate‐specification. Whereas the production of SOM+ cells peaks early and subsequently declines, PV+ cells are continuously generated throughout embryonic neurogenesis. ChCs are preferentially born at the very late embryonic stage.
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Developmental origins and diversity of cortical interneurons. (a) Cortical interneurons in mouse are derived from progenitor cells located in the proliferative zones of the ventral telencephalon, specifically in the medial ganglionic eminence (MGE), caudal ganglionic eminence (CGE) and preoptic area (PoA). LGE, lateral ganglionic eminence; Ctx, cortex; OB, olfactory bulb. (b) The major source of interneurons is the MGE, generating ~70% of cortical interneurons comprised of two nonoverlapping populations expressing parvalbumin (PV) and somatostatin (SOM). Approximately 30% of cortical interneurons are a heterogeneous group of cells generated by the CGE, all of which express 5HTR (serotonin receptor)‐3A as well as either vasointestinal peptide (VIP) or reelin. In addition, CGE is the main source of calretinin (CR) and cholecystokinin (CCK)‐expressing cells. The PoA generates ~10% of interneurons a fraction of which express neuropeptide Y (NPY), neuronal nitric oxide synthase (nNOS), and SOM. (c) Evolution of the mammalian brain from lower mammals such as mouse to primates such as macaque monkey and human. Mouse and macaque monkey diverged from human ~100 and ~25 m.y.a. (million years ago), respectively. (d) Developmental origins of cortical interneurons across mammalian species. E, embryonic day; GW, gestation week.
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