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.
Article and author information
Author details
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.
Reviewing Editor
- Anne West, Duke University School of Medicine, United States
Publication history
- Received: August 18, 2016
- Accepted: December 7, 2016
- Accepted Manuscript published: December 9, 2016 (version 1)
- Version of Record published: December 19, 2016 (version 2)
Copyright
© 2016, Zechel et al.
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.
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