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 GABAA receptor expression for the formation and function of presynaptic inhibitory synapses. Specifically, early α3-subunit-containing GABAA (GABAAα3) receptors are a key developmental organizer. Before eye opening, GABAAα3 gives way to GABAAα1 at individual BC presynaptic inhibitory synapses. The developmental downregulation of GABAAα3 is independent of GABAAα1 expression. Importantly, lack of early GABAAα3 impairs clustering of GABAAα1 and formation of functional GABAA synapses across mature BC terminals. This impacts the sensitivity of visual responses transmitted through the circuit. Lack of early GABAAα3 also perturbs aggregation of LRRTM4, the organizing protein at GABAergic synapses of rod BC terminals, and their arrangement of output ribbon synapses.