Intrinsic and Extrinsic Mechanisms Control the Termination of Cortical Interneuron Migration

Abstract

During development, neurons migrate from their site of origin to their final destinations. Upon reaching this destination, the termination of their migration is crucial for building functional architectures such as laminated structures and nuclei. How this termination is regulated, however, is not clear. Here, we investigated the contribution of cell-intrinsic mechanisms and extrinsic factors. Using GAD67-GFP knock-in mice and in utero electroporation cell labeling, we visualized GABAergic neurons and analyzed their motility in vitro. We find that the motility of GABAergic neurons in cortical slices gradually decreases as development proceeds and is almost abolished by the end of the first postnatal week. Consistent with this, a reduction of embryonic interneuron motility occurred in dissociated cultures. This is in part due to cell-intrinsic mechanisms, as a reduction in motility is observed during long-term culturing on glial feeder cells. Cell-intrinsic regulation is further supported by observations that interneurons labeled in early stages migrated more actively than those labeled in late stages in the same cortical explant. We found evidence suggesting that upregulation of the potassium-chloride cotransporter KCC2 underlies this intrinsic regulation. Reduced motility is also observed when embryonic interneurons are plated on postnatal cortical feeder cells, suggesting extrinsic factors derived from the postnatal cortex too contribute to termination. These factors should include secreted molecules, as cultured postnatal cortical cells could exercise this effect without directly contacting the interneuron. These findings suggest that intrinsic mechanisms and extrinsic factors coordinate to reduce the motility of migrating neurons, thereby leading to the termination of migration.

PlexinD1 signaling controls morphological changes and migration termination in newborn neurons

“…Therefore, it is possible that the timing of PlexinD1 downregulation, which controls FLP formation and neuronal migration termination in the OB, is intrinsically programmed in each new neuron or its parental NSC in the V‐SVZ. The timing of migration termination and the subsequent integration of cortical interneurons are also intrinsically determined by cellular age (Bortone & Polleux, ; Inamura et al , ; Southwell et al , ). In contrast, interestingly, our transplantation study showed that the duration and distance of migration are not strictly programmed in each V‐SVZ‐derived new neuron (Fig ).…”

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

“…Most MGE-derived interneurons in the adult neocortex express either somatostatin (SST) or parvalbumin (PV) (Fogarty et al, 2007;Miyoshi et al, 2007). A majority of these interneurons complete their tangential migration into the neocortex by birth (Miyoshi and Fishell, 2011;Inamura et al, 2012). However, PV protein or Pvalb mRNA is not expressed until much later, indicating that the expression of PV or Pvalb is a useful marker of maturation for this lineage of cells.…”

Cellular and molecular mechanisms controlling the migration of neocortical interneurons

“…The mechanisms that regulate the expression of KCC2 remain unknown. One possibility is that interneurons turn on KCC2 expression as part of an intrinsic program of maturation (Inamura et al, 2012). This would allow interneurons to cease migration progressively, depending on their birthdate (Hevner et al, 2004;Pla et al, 2006).…”