GABAA receptors (GABAA-Rs) play critical roles in brain development and synchronization of neural network activity. While synaptic GABAA-Rs can exert rapid inhibition, the extrasynaptic GABAA-Rs can tonically inhibit neuronal activity due to constant activation by ambient GABA. The δ subunit-containing GABAA-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-GABAA-Rs have been well characterized, the molecular interacting partners of the δ-GABAA-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-GABAA-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-GABAA-Rs in cerebellar granule neurons. Together, our studies identified TTR as a novel regulator of the δ-GABAA-Rs.