Identification of transthyretin as a novel interacting partner for the δ subunit of GABA(A) receptors

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.