KCC2 expression promotes the termination of cortical interneuron migration in a voltage-sensitive calcium-dependent manner.
The molecular mechanisms controlling the termination of cortical interneuron migration are unknown. Here, we demonstrate that, prior to synaptogenesis, migrating interneurons change their responsiveness to ambient GABA from a motogenic to a stop signal. We found that, during migration into the cortex, ambient GABA and glutamate initially stimulate the motility of interneurons through both GABA(A) and AMPA/NMDA receptor activation. Once in the cortex, upregulation of the potassium-chloride cotransporter KCC2 is both necessary and sufficient to reduce interneuron motility through its ability to reduce membrane potential upon GABA(A) receptor activation, which decreases the frequency of spontaneous intracellular calcium transients initiated by L-type voltage-sensitive calcium channel (VSCC) activation. Our results suggest a mechanism whereby migrating interneurons determine the relative density of surrounding interneurons and principal cells through their ability to sense the combined extracellular levels of ambient glutamate and GABA once GABA(A) receptor activation becomes hyperpolarizing.
Neurobiology Curriculum, Neuroscience Center, Department of Pharmacology, University of North Carolina, Chapel Hill, 115 Mason Farm Road, Chapel Hill, NC 27599-7250, USA.
Dante
D
Bortone
Franck
F
Polleux
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001640:Bicuculline / Q000031:analogs & derivatives / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000502:physiology*; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002540:Cerebral Cortex / Q000166:cytology*; D018274:Electroporation / Q000379:methods; D004622:Embryo, Mammalian; D005260:Female; D018682:GABA Agents / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D018698:Glutamic Acid / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D007395:Interneurons / Q000502:physiology*; D060850:LIM-Homeodomain Proteins; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008954:Models, Biological; D009118:Muscimol / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics; D009543:Nifedipine / Q000494:pharmacology; D009924:Organ Culture Techniques; D011247:Pregnancy; D011810:Quinoxalines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D017384:Sequence Deletion; D027981:Symporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology; D020866:omega-Conotoxin GVIA / Q000494:pharmacology; D000096922:K Cl- Cotransporters
D001640:Bicuculline; D002118:Calcium; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D018682:GABA Agents; D018698:Glutamic Acid; D049452:Green Fluorescent Proteins; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D008869:Microtubule-Associated Proteins; D009118:Muscimol; D009419:Nerve Tissue Proteins; D009543:Nifedipine; D011810:Quinoxalines; D034741:RNA, Small Interfering; D016194:Receptors, N-Methyl-D-Aspartate; D027981:Symporters; D014157:Transcription Factors; D014633:Valine; D005680:gamma-Aminobutyric Acid; D020866:omega-Conotoxin GVIA; D000096922:K Cl- Cotransporters; C498504:LHX6 protein, mouse; C079240:Mtap2 protein, mouse; C485184:enhanced green fluorescent protein; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C017069:bicuculline methiodide; C056639:2-amino-5-phosphopentanoic acid