Like many travellers, migrating cortical interneurons need to know when their journey is complete; however, the mechanisms that terminate their migration are largely unknown. Bortone and Polleux now show that changes in interneurons' response to extracellular GABA (-aminobutyric acid) as a result of upregulation of the K⁺-Cl^- co-transporter KCC2 (also known as SLC12A5) cause interneurons to halt their migration.

The migration of developing interneurons from the medial and caudal ganglionic eminences (MGE and CGE) to the cortical plate is characterized by intermittent pauses. The authors showed that the frequency and duration of these pauses increase during the first postnatal week, by the end of which migration is complete. Experiments in which mouse MGE explants at different stages of maturation were cultured on a substrate of dissociated pyramidal neurons suggested that intrinsic changes during interneurons' maturation render them more responsive to extracellular 'stop' signals.

Interneurons express GABA_A receptors, making GABA a plausible candidate stop signal. Indeed, when GABA was added to the culture the average frequency and duration of pausing increased. As the extent of pausing in response to GABA varied between migrating interneurons, the authors could correlate the response of individual interneurons with the expression of intrinsic factors that affect interneurons' reaction to GABA. They considered the possibility that the response to GABA is affected by the membrane Cl^- gradient, which is determined by the expression of KCC2 and establishes whether a cell becomes depolarized (low KCC2) or hyperpolarized (high KCC2) in response to GABA.

The authors showed that KCC2 expression is progressively upregulated in vivo several days after interneurons reach the cortex, coinciding with the end of interneuron migration. In their culture system only interneurons with high KCC2 expression stopped migrating in response to GABA, a response that relies on GABA_A receptor activation. Interestingly, blocking GABA_A activation increased pausing in neurons expressing low KCC2, suggesting that GABA_A activation in these cells actually stimulates migration. Furthermore, when KCC2 was overexpressed in MGE explants exposed to GABA the number of neurons halting their migration was increased, whereas knocking down KCC2 expression had the opposite effect.

These findings suggest that in neurons expressing low levels of KCC2, GABA_A-mediated depolarization stimulates migration, whereas when KCC2 expression is high GABA_A-mediated hyperpolarization halts migration. Indeed, forced hyperpolarization through the overexpression of an inward-rectifying K⁺ channel replicated the effects of high KCC2.

How does GABA-mediated depolarization or hyperpolarization influence migration? The authors showed that knocking down KCC2 increased the frequency of Ca²⁺ transients in cultured interneurons, whereas overexpressing KCC2 decreased their frequency. When the authors chelated intracellular Ca²⁺ the interneurons stopped migrating, confirming that the intracellular Ca²⁺ transients are required for migration. The authors went on to confirm that GABA-mediated depolarization triggers Ca²⁺ entry through L-type Ca²⁺ channels.

Next the authors considered whether other signals that depolarize migrating interneurons might influence their migration. Indeed, blocking ionotropic glutamate receptors increased the percentage of neurons halting their migration in response to GABA, indicating that both glutamate- and GABA-mediated depolarization stimulate migration early in development.

These findings suggest that once GABA becomes hyperpolarizing, migrating interneurons integrate the ambient levels of GABA and glutamate to determine when to stop migrating. Determining the factors that regulate KCC2 expression will provide further insight into the temporal control of this process.

Author: Katherine Whalley - Copyright © 2009 Nature Publishing Group, a division of MacMillan Publishers Limited; used with permission