The potassium chloride cotransporter KCC-2 coordinates development of inhibitory neurotransmission and synapse structure in Caenorhabditis elegans

J Neurosci. 2009 Aug 12;29(32):9943-54. doi: 10.1523/JNEUROSCI.1989-09.2009.

Abstract

Chloride influx through GABA-gated chloride channels, the primary mechanism by which neural activity is inhibited in the adult mammalian brain, depends on chloride gradients established by the potassium chloride cotransporter KCC2. We used a genetic screen to identify genes important for inhibition of the hermaphrodite-specific motor neurons (HSNs) that stimulate Caenorhabditis elegans egg-laying behavior and discovered mutations in a potassium chloride cotransporter, kcc-2. Functional analysis indicates that, like mammalian KCCs, C. elegans KCC-2 transports chloride, is activated by hypotonic conditions, and is inhibited by the loop diuretic furosemide. KCC-2 appears to establish chloride gradients required for the inhibitory effects of GABA-gated and serotonin-gated chloride channels on C. elegans behavior. In the absence of KCC-2, chloride gradients appear to be altered in neurons and muscles such that normally inhibitory signals become excitatory. kcc-2 is transcriptionally upregulated in the HSN neurons during synapse development. Loss of KCC-2 produces a decrease in the synaptic vesicle population within mature HSN synapses, which apparently compensates for a lack of HSN inhibition, resulting in normal egg-laying behavior. Thus, KCC-2 coordinates the development of inhibitory neurotransmission with synapse maturation to produce mature neural circuits with appropriate activity levels.

Publication types

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

MeSH terms

  • Animals
  • Caenorhabditis elegans / physiology*
  • Caenorhabditis elegans Proteins / metabolism
  • Chlorides / metabolism
  • Furosemide / pharmacology
  • Hypotonic Solutions
  • K Cl- Cotransporters
  • Motor Neurons / physiology
  • Muscles / physiology
  • Mutation
  • Receptors, G-Protein-Coupled / metabolism
  • Sequence Homology
  • Sexual Behavior, Animal / physiology
  • Sodium Potassium Chloride Symporter Inhibitors / pharmacology
  • Symporters / antagonists & inhibitors
  • Symporters / genetics
  • Symporters / metabolism*
  • Synapses / physiology*
  • Synaptic Transmission / physiology*
  • Synaptic Vesicles / physiology
  • Up-Regulation

Substances

  • Caenorhabditis elegans Proteins
  • Chlorides
  • EGL-47 protein, C elegans
  • Hypotonic Solutions
  • Receptors, G-Protein-Coupled
  • Sodium Potassium Chloride Symporter Inhibitors
  • Symporters
  • Furosemide