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.
Highlights
Interneurons of the mammalian neocortex are generated in transient neurogenic structures of the embryonic ventral forebrain, including the lateral, medial, and caudal ganglionic eminences (LGE, MGE, and CGE, respectively), the preoptic area (POA) and the septum (Bartolini et al, 2013; Wonders and Anderson, 2006)
In order to investigate the role of thalamo-cortical axon (TCA) in tangential migration and radial dispersion of MGE-derived interneurons, we took advantage of the Gbx2 mutant mouse, which lacks TCAs as a consequence of abnormal thalamic development (Hevner et al, 2002; Wassarman et al, 1997) (Figure 1—figure supplement 1)
Our results indicate that radial dispersion of GABAergic interneurons requires signals derived from TCAs and that this requirement can be circumvented by depletion of KCC2
Summary
Interneurons of the mammalian neocortex are generated in transient neurogenic structures of the embryonic ventral forebrain, including the lateral, medial, and caudal ganglionic eminences (LGE, MGE, and CGE, respectively), the preoptic area (POA) and the septum (Bartolini et al, 2013; Wonders and Anderson, 2006). Several molecular signals have been identified that regulate the tangential migration and dispersion of interneurons towards and within the neocortex, including Neuregulin-1 (NRG1) (Flames et al, 2004), hepatocyte growth factor (HGF) (Powell et al, 2001), glial cell line-derived neurotrophic factor (GDNF) (Canty et al, 2009; Pozas and Ibanez, 2005) and the chemokine Cxcl (LopezBendito et al, 2008). After their tangential dispersion through the neocortex, interneurons switch their mode of migration from tangential to radial and invade the cortical plate.
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