TRPA1 channels regulate astrocyte resting calcium and inhibitory synapse efficacy through GAT-3

TY - JOUR

T1 - TRPA1 channels regulate astrocyte resting calcium and inhibitory synapse efficacy through GAT-3

AU - Shigetomi, Eiji

AU - Tong, Xiaoping

AU - Kwan, Kelvin Y.

AU - Corey, David P.

AU - Khakh, Baljit S.

N1 - Funding Information: cultures and to S. Kracun for molecular biology help and discussions. Thanks to M. Nedergaard for discussions during the early stages of this project. Special thanks to members of the Astrocyte Biology and Biophysics Affinity Group at UCLA for discussions. Thanks to A. Patapoutian (mouse TRPA1; The Scripps Research Institute), D. Julius (rat TRPA1; University of California San Francisco) and Y. Gwack (mCherry; University of California Los Angeles) for sharing plasmids. Thanks to N. Brecha (University of California Los Angeles) for GAT-1 and GAT-3 antibodies. Our work was supported mainly by US National Institutes of Health National Institute of Neurological Disorders and Stroke grant NS060677 and partly by grants NS071292 and NS063186, the Whitehall Foundation and a Stein-Oppenheimer Endowment Award (to B.S.K.).

PY - 2012/1

Y1 - 2012/1

N2 - Astrocytes contribute to the formation and function of synapses and are found throughout the brain, where they show intracellular store-mediated Ca 2+ signals. Here, using a membrane-tethered, genetically encoded calcium indicator (Lck-GCaMP3), we report the serendipitous discovery of a new type of Ca 2+ signal in rat hippocampal astrocyte-neuron cocultures. We found that Ca 2+ fluxes mediated by transient receptor potential A1 (TRPA1) channels gave rise to frequent and highly localized 'spotty' Ca 2+ microdomains near the membrane that contributed appreciably to resting Ca 2+ in astrocytes. Mechanistic evaluations in brain slices showed that decreases in astrocyte resting Ca 2+ concentrations mediated by TRPA1 channels decreased interneuron inhibitory synapse efficacy by reducing GABA transport by GAT-3, thus elevating extracellular GABA. Our data show how a transmembrane Ca 2+ source (TRPA1) targets a transporter (GAT-3) in astrocytes to regulate inhibitory synapses.

AB - Astrocytes contribute to the formation and function of synapses and are found throughout the brain, where they show intracellular store-mediated Ca 2+ signals. Here, using a membrane-tethered, genetically encoded calcium indicator (Lck-GCaMP3), we report the serendipitous discovery of a new type of Ca 2+ signal in rat hippocampal astrocyte-neuron cocultures. We found that Ca 2+ fluxes mediated by transient receptor potential A1 (TRPA1) channels gave rise to frequent and highly localized 'spotty' Ca 2+ microdomains near the membrane that contributed appreciably to resting Ca 2+ in astrocytes. Mechanistic evaluations in brain slices showed that decreases in astrocyte resting Ca 2+ concentrations mediated by TRPA1 channels decreased interneuron inhibitory synapse efficacy by reducing GABA transport by GAT-3, thus elevating extracellular GABA. Our data show how a transmembrane Ca 2+ source (TRPA1) targets a transporter (GAT-3) in astrocytes to regulate inhibitory synapses.

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U2 - 10.1038/nn.3000

DO - 10.1038/nn.3000

M3 - Article

C2 - 22158513

SN - 1097-6256

VL - 15

SP - 70

EP - 80

JO - Nature neuroscience

JF - Nature neuroscience

IS - 1

ER -