Thalamo-cortical axons regulate the radial dispersion of neocortical GABAergic interneurons

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Abstract

Neocortical GABAergic interneuron migration and thalamo-cortical axon (TCA) pathfinding follow similar trajectories and timing, suggesting they may be interdependent. The mechanisms that regulate the radial dispersion of neocortical interneurons are incompletely understood. Here we report that disruption of TCA innervation, or TCA-derived glutamate, affected the laminar distribution of GABAergic interneurons in mouse neocortex, resulting in abnormal accumulation in deep layers of interneurons that failed to switch from tangential to radial orientation. Expression of the KCC2 cotransporter was elevated in interneurons of denervated cortex, and KCC2 deletion restored normal interneuron lamination in the absence of TCAs. Disruption of interneuron NMDA receptors or pharmacological inhibition of calpain also led to increased KCC2 expression and defective radial dispersion of interneurons. Thus, although TCAs are not required to guide the tangential migration of GABAergic interneurons, they provide crucial signals that restrict interneuron KCC2 levels, allowing coordinated neocortical invasion of TCAs and interneurons.

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Sabrina Zechel

Department of Neuroscience, Karolinska Institute, Stockholm, Sweden

Competing interests
The authors declare that no competing interests exist.
Yasushi Nakagawa

Department of Neuroscience, University of Minnesota Medical School, Minneapolis, United States

Competing interests
The authors declare that no competing interests exist.
Carlos F Ibáñez

Department of Neuroscience, Karolinska Institute, Stockholm, Sweden

For correspondence
carlos.ibanez@ki.se

Competing interests
The authors declare that no competing interests exist.

Funding

Knut och Alice Wallenbergs Stiftelse

Carlos F Ibáñez

Karolinska Institutet

Carlos F Ibáñez

National University of Singapore

Carlos F Ibáñez

Wenner-Gren Foundation

Sabrina Zechel

Vetenskapsrådet

Carlos F Ibáñez

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal protocols (N27/15; N173/15 and N240/13) were approved by Stockholms Norra Djurförsöksetiska nämnd and are in accordance with the ethical guidelines of the Karolinska Institute.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.