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  • Review Article
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Genetic and activity-dependent mechanisms underlying interneuron diversity

Nature Reviews Neuroscience volume 18, pages 299–309 (2017)Cite this article

Subjects

Key Points

  • Neuronal diversity has evolved to support complex brain function, and this is exemplified in the great diversity of cortical inhibitory interneuron subtypes.

  • The developmental origins of interneuron diversity are thought to be attributable either to the early specification of specific progenitors (the progenitor specification model) or to progressive specification through a combination of intrinsic genetic programming and later modification by environmental cues (the progressive specification model).

  • Cortical interneurons have been shown to be engaged in and contribute to neuronal activity present at every stage in nervous system development. Dependent on the stage, these activities can be spontaneous uncorrelated events or rhythmic oscillations generated by transient or nascent neuronal networks.

  • Cortical interneuron activity is important for the differentiation of subtype-specific attributes such as layer settling position, morphology, synaptic specificity and molecular markers.

  • Key aspects of interneuron development are dependent on activity-dependent mechanisms including distinct calcium signalling pathways and associated activity-mediated gene expression.

  • Although it is now clear that activity supports the specification of cortical interneurons, the precise balance between developmental predisposition and environmental specialization remains unclear. The rapid expansion and use of new molecular techniques promise to soon provide us with a more complete understanding of how interneuron fate is specified. It will also clarify the link between crucial developmental periods and the plasticity within brain circuits required for learning and memory.

Abstract

The proper construction of neural circuits requires the generation of diverse cell types, their distribution to defined regions, and their specific and appropriate wiring. A major objective in neurobiology has been to understand the molecular determinants that link neural birth to terminal specification and functional connectivity, a task that is especially daunting in the case of cortical interneurons. Considerable evidence supports the idea that an interplay of intrinsic and environmental signalling is crucial to the sequential steps of interneuron specification, including migration, selection of a settling position, morphogenesis and synaptogenesis. However, when and how these influences merge to support the appropriate terminal differentiation of different classes of interneurons remains uncertain. In this Review, we discuss a wealth of recent findings that have advanced our understanding of the developmental mechanisms that contribute to the diversification of interneurons and suggest areas of particular promise for further investigation.

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Figure 1: Cortical interneuron diversity.
Figure 2: Connectivity of the four main classes of cortical interneurons.
Figure 3: Models of cortical interneuron development.
Figure 4: Activity-dependent mechanisms in developing cortical interneurons.

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Acknowledgements

The authors thank X. Jaglin, T. Petros and the remaining members of the Fishell laboratory for their support, thoughtful discussions and critical reading on the manuscript. The authors apologize to colleagues whose research was not cited owing to the broad scope and space limitations of this Review. The Fishell laboratory is supported by grants from the US National Institutes of Health (NIH) (5R01NS081287, 5P01NS074972) and the Simons Foundation (274578, 383356). B.W. was partially supported by the NIH training program at New York University (NYU) for Molecular, Cellular, and Translational Neuroscience training grant (5T32NS086750).

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  1. Department of Neuroscience and Physiology, New York University (NYU) Neuroscience Institute, Smilow Research Center, NYU School of Medicine, 522 First Avenue, New York, 10016, New York, USA

    Brie Wamsley & Gord Fishell

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  1. Brie Wamsley
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Correspondence to Gord Fishell.

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Neural ensembles

Select groups of connected neurons within a network whose synchronous activity is highly correlated to aspects of particular behaviours.

Ganglionic eminence

The name given to any one of the three transient embryonic proliferative zones that line the floor of the lateral ventricles. These zones give rise to almost all inhibitory projection neurons and interneurons that populate the cortex and basal ganglia.

Multipotent progenitors

Proliferative cells that have the potential to give rise to distinct cell types on the basis of differences in developmental stage, spatial position, environmental cues and mode of division.

Tangential migration

A mode of migration used by newly generated inhibitory interneurons that originate within the eminences. These interneurons migrate from the ventricular progenitor zones into the overlying mantle and disperse to populate various brain structures. Tangentially migrating interneurons from the medial and caudal ganglionic eminences populate cortical and subcortical structures, whereas those from the lateral ganglionic eminence populate the olfactory bulb.

Radial migration

Radial glia-guided migration used by both interneuron and projection neurons primarily to position themselves within the cortical plate.

Calcium transients

Transient increases in the level of intracellular calcium generally within a 1–5 Hz frequency. These are typically optically recorded within the cell soma through fluorescence calcium indicators; however, dendritic and axonal recordings have also been recorded.

Coincidence detection

A mechanism whereby the coordinate timing of presynaptic and postsynaptic stimuli translates temporal and spatial differences in arriving synaptic transmission into changes in the probability of action potential generation and/or synaptic plasticity (including Hebbian strengthening, long-term potentiation and long-term depression) within the target neuron.

Cortical early network oscillations

An early rhythmic pattern of synchronized increases in membrane potential among large groups of neurons recorded in vitro in neocortical slices. The oscillations are dependent on glutamate, and those recorded in vitro are slower and of higher voltages than early gamma oscillations observed in vivo.

Giant depolarizing potentials

A form of synchronized neuronal depolarization patterns that supplant cortical early network oscillations during development and that are dependent on the actions of excitatory GABA. Each event is shorter than an early network oscillation but similar in magnitude.

Spindle bursts

Oscillatory events observed in vivo in the neonatal cortex. They are produced by the synchronized depolarization of a small localized group of neurons and can be evoked by sensory stimuli. Spindle bursts are slower events compared with early gamma oscillations.

Early gamma oscillations

One of the premier oscillatory events observed in vivo in the neonatal cortex. They are brief synchronized events evoked spontaneously and by feedforward excitation from the thalamus. Early gamma oscillations are transient events during the first postnatal week that are replaced by adult gamma oscillations dependent on parvalbumin-expressing interneuron inhibition.

Critical windows

Distinct time frames within the perinatal period when particular transient activity-dependent developmental events have a lasting impact on the functional behaviour of particular classes of neurons or neuronal ensembles.

Immediate early genes

(IEGs). A set of genes, the expression of which is induced within minutes to hours following neuronal depolarization.

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Wamsley, B., Fishell, G. Genetic and activity-dependent mechanisms underlying interneuron diversity. Nat Rev Neurosci 18, 299–309 (2017). https://doi.org/10.1038/nrn.2017.30

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