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

Neocortical GABAergic interneuronmigration and thalamo-cortical axon (TCA) pathfindingfollow similar trajectories and timing, suggesting they may be interdependent. The mechanisms that regulate the radial dispersion of neocortical interneuronsare incompletely understood. Here we report that disruption of TCA innervation, or TCA-derived glutamate, affected the laminar distribution of GABAergic interneuronsin mouse neocortex, resulting in abnormal accumulation in deep layers of interneuronsthat failed to switch from tangentialto radial orientation. Expression of the KCC2 cotransporterwas elevated in interneuronsof denervated cortex, and KCC2 deletion restored normal interneuronlamination in the absence of TCAs. Disruption of interneuronNMDA receptors or pharmacological inhibition of calpainalso led to increased KCC2 expression and defective radial dispersion of interneurons. Thus, although TCAs are not required to guide the tangentialmigration of GABAergic interneurons, they provide crucial signals that restrict interneuronKCC2 levels, allowing coordinated neocortical invasion of TCAs and interneurons.