Transient expression of a GABA receptor subunit during early development is critical for inhibitory synapse maturation and function

Developing neural circuits, including GABAergic circuits, switch receptor types. But the role of early GABA receptor expression for establishment of functional inhibitory circuits remains unclear. Tracking the development of GABAergic synapses across axon terminals of retinal bipolar cells (BCs), we uncovered a crucial role of early GABA_A receptor expression for the formation and function of presynaptic inhibitory synapses. Specifically, early α3-subunit-containing GABA_A (GABA_Aα3) receptors are a key developmental organizer. Before eye opening, GABA_Aα3 gives way to GABA_Aα1 at individual BC presynaptic inhibitory synapses. The developmental downregulation of GABA_Aα3 is independent of GABA_Aα1 expression. Importantly, lack of early GABA_Aα3 impairs clustering of GABA_Aα1 and formation of functional GABA_A synapses across mature BC terminals. This impacts the sensitivity of visual responses transmitted through the circuit. Lack of early GABA_Aα3 also perturbs aggregation of LRRTM4, the organizing protein at GABAergic synapses of rod BC terminals, and their arrangement of output ribbon synapses.