KCC2 expression promotes the termination of cortical interneuron migration in a voltage-sensitive calcium-dependent manner

Neuron. 2009 Apr 16;62(1):53-71. doi: 10.1016/j.neuron.2009.01.034.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Animals, Newborn
  • Bicuculline / analogs & derivatives
  • Bicuculline / pharmacology
  • Calcium / metabolism
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels, L-Type / physiology*
  • Cell Movement / drug effects
  • Cell Movement / physiology*
  • Cerebral Cortex / cytology*
  • Electroporation / methods
  • Embryo, Mammalian
  • Female
  • GABA Agents / pharmacology
  • Gene Expression Regulation / drug effects
  • Glutamic Acid / pharmacology
  • Green Fluorescent Proteins / genetics
  • Homeodomain Proteins / genetics
  • Interneurons / physiology*
  • LIM-Homeodomain Proteins
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Microtubule-Associated Proteins / metabolism
  • Models, Biological
  • Muscimol / pharmacology
  • Nerve Tissue Proteins / genetics
  • Nifedipine / pharmacology
  • Organ Culture Techniques
  • Pregnancy
  • Quinoxalines / pharmacology
  • RNA, Small Interfering / pharmacology
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Sequence Deletion
  • Symporters / antagonists & inhibitors
  • Symporters / genetics
  • Symporters / metabolism*
  • Transcription Factors
  • Valine / analogs & derivatives
  • Valine / pharmacology
  • gamma-Aminobutyric Acid / pharmacology
  • omega-Conotoxin GVIA / pharmacology

Substances

  • Calcium Channel Blockers
  • Calcium Channels, L-Type
  • GABA Agents
  • Homeodomain Proteins
  • LHX6 protein, mouse
  • LIM-Homeodomain Proteins
  • Microtubule-Associated Proteins
  • Mtap2 protein, mouse
  • Nerve Tissue Proteins
  • Quinoxalines
  • RNA, Small Interfering
  • Receptors, N-Methyl-D-Aspartate
  • Symporters
  • Transcription Factors
  • enhanced green fluorescent protein
  • potassium-chloride symporters
  • 2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline
  • Green Fluorescent Proteins
  • Muscimol
  • Glutamic Acid
  • bicuculline methiodide
  • gamma-Aminobutyric Acid
  • 2-amino-5-phosphopentanoic acid
  • omega-Conotoxin GVIA
  • Valine
  • Nifedipine
  • Calcium
  • Bicuculline