GABA A receptors (GABA A -Rs) play critical roles in brain development and synchronization of neural network activity. While synaptic GABA A -Rs can exert rapid inhibition, the extrasynaptic GABA A -Rs can tonically inhibit neuronal activity due to constant activation by ambient GABA. The δ subunit-containing GABA A -Rs are expressed abundantly in the cerebellum, hippocampus and thalamus to mediate the major tonic inhibition in the brain. While electrophysiological and pharmacological properties of the δ-GABA A -Rs have been well characterized, the molecular interacting partners of the δ-GABA A -Rs are not clearly defined. Here, using a yeast two-hybrid screening assay, we identified transthyretin (TTR) as a novel regulatory molecule for the δ-GABA A -Rs. Knockdown of TTR in cultured cerebellar granule neurons significantly decreased the δ receptor expression; whereas overexpressing TTR in cortical neurons increased the δ receptor expression. Electrophysiological analysis confirmed that knockdown or overexpression of TTR in cultured neurons resulted in a corresponding decrease or increase of tonic currents. Furthermore, in vivo analysis of TTR-/- mice revealed a significant decrease of the surface expression of the δ-GABA A -Rs in cerebellar granule neurons. Together, our studies identified TTR as a novel regulator of the δ-GABA A -Rs.
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