The Potassium Chloride Cotransporter KCC-2 Coordinates Development of Inhibitory Neurotransmission and Synapse Structure in Caenorhabditis elegans

• Published in: The Journal of neuroscience Vol. 29; no. 32; pp. 9943 - 9954
• Main Authors: Tanis, Jessica E, Bellemer, Andrew, Moresco, James J, Forbush, Biff, Koelle, Michael R
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 12.08.2009; Society for Neuroscience
• Subjects: 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
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.1989-09.2009

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.