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The Journal of Neuroscience, August 12, 2009, 29(32):9943-9954; doi:10.1523/JNEUROSCI.1989-09.2009

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

Jessica E. Tanis,^1,2 Andrew Bellemer,¹ James J. Moresco,¹ Biff Forbush,² and Michael R. Koelle¹

Departments of ¹Molecular Biophysics and Biochemistry and ²Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520

Correspondence should be addressed to Dr. Michael R. Koelle, Yale University School of Medicine, Department of Molecular Biophysics and Biochemistry, 333 Cedar Street, SHM CE30, New Haven, CT 06520-8024. Email: michael.koelle{at}yale.edu

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.

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Received April 27, 2009; revised June 24, 2009; accepted July 1, 2009.

Correspondence should be addressed to Dr. Michael R. Koelle, Yale University School of Medicine, Department of Molecular Biophysics and Biochemistry, 333 Cedar Street, SHM CE30, New Haven, CT 06520-8024. Email: michael.koelle{at}yale.edu

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