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 receptor expression for the formation and function of presynaptic inhibitory synapses. Specifically, early α3-subunit-containing GABA (GABAα3) receptors are a key developmental organizer. Before eye opening, GABAα3 gives way to GABAα1 at individual BC presynaptic inhibitory synapses. The developmental downregulation of GABAα3 is independent of GABAα1 expression. Importantly, lack of early GABAα3 impairs clustering of GABAα1 and formation of functional GABA synapses across mature BC terminals. This impacts the sensitivity of visual responses transmitted through the circuit. Lack of early GABAα3 also perturbs aggregation of LRRTM4, the organizing protein at GABAergic synapses of rod BC terminals, and their arrangement of output ribbon synapses.