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

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.DOI: http://dx.doi.org/10.7554/eLife.20770.001

The thalamus regulates retinoic acid signaling and development of parvalbumin interneurons in postnatal mouse prefrontal cortex

“…there was an increase in the density of LHX6-positive cells in layer 6 and below, and a decrease in the middle layers ( Fig.6F), while the total density was not significantly different between the two genotypes ( Fig.6G). These results on the neonatal PFC are remarkably similar to a recent report on sensory and motor cortex of thalamus-specific Gbx2 mutant mice (Zechel et al, 2016). Thus, there is an early, cortex-wide role of thalamocortical projections in controlling the radial distribution of MGE-derived interneurons.…”

“…The current study also revealed an early role of the thalamus in regulating the radial positioning of MGE-derived interneurons in neonatal PFC. The altered positioning of interneurons was highly reminiscent of what was found in sensory and motor areas 12 .…”

“…In sensory cortex, it is known that thalamocortical afferents affect the development of interneurons by a variety of mechanisms (Sugiyama et al, 2008;Marques-Smith et al, 2016;Tuncdemir et al, 2016;Zechel et al, 2016). At P21, densities of Pvalb-and Sst-expressing interneurons in medial PFC, specifically in the middle layers and not in the most superficial and the deepest layers, were significantly reduced in Gbx2 mutant mice ( Fig.6A-C).…”

“…In sensory cortex, thalamocortical afferents affect the development of interneurons by a variety of mechanisms [12][13][14][15] . However, roles of the thalamus in the development of PFC interneurons are unknown.…”

“…Development of cortical interneurons is regulated by both intrinsic and extrinsic mechanisms (Chu and Anderson, 2015;Wamsley and Fishell, 2017). One key extrinsic cue is the input from the thalamus, which regulates migration and maturation of cortical interneurons both prenatally and postnatally in mice (Sugiyama et al, 2008;Marques-Smith et al, 2016;Tuncdemir et al, 2016;Zechel et al, 2016). However, most studies addressing the role of the thalamic input in interneuron development have been performed on primary visual or somatosensory cortex, leaving the mechanisms in PFC understudied.…”