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

Astrocytes contribute to the formation and function of synapses and are found throughout the brain where they display intracellular store mediated Ca(2+) signals. Here, using a membrane tethered genetically encoded calcium indicator (Lck-GCaMP3), we report the serendipitous discovery of a novel Ca(2+) signal in rat hippocampal astrocyte-neuron co-cultures. We found that TRPA1 channel mediated Ca(2+) fluxes give rise to frequent and highly localised near membrane “spotty” Ca(2+) microdomains that contribute significantly to resting Ca(2+) levels of astrocytes. Mechanistic evaluations in brain slices show that decreasing astrocyte resting Ca(2+) levels mediated by TRPA1 channels decreased interneuron inhibitory synapse efficacy by reducing GABA transport via GAT-3, thus elevating extracellular GABA levels. Our data indicate how a novel transmembrane Ca(2+) source (TRPA1) targets a transporter (GAT-3) in astrocytes to regulate inhibitory synapses.