eNeuro. 2023 Jul 24:ENEURO.0158-23.2023. doi: 10.1523/ENEURO.0158-23.2023. Online ahead of print.
AMPA receptors (AMPARs) are the major mediators of fast excitatory neurotransmission in the retina as in other parts of the brain. In most neurons, the synaptic targeting, pharmacology and function of AMPARs is influenced by auxiliary subunits including the transmembrane AMPA receptor regulatory proteins (TARPs). However, it is unclear which TARP subunits are present at retinal synapses and how they influence receptor localization and function. Here, we show that TARPɣ2 (stargazin) is associated with AMPARs in the synaptic layers of the mouse, rabbit, macaque and human retina. In most species, TARPɣ2 expression was high where starburst amacrine cells (SACs) ramify and transcriptomic analyses suggest correspondingly high gene expression in mouse and human SACs. Synaptic expression of GluA2, GluA3 and GluA4 was significantly reduced in a mouse mutant lacking TARPɣ2 expression (stargazer mouse; stg), whereas GluA1 levels were unaffected. AMPAR mediated light-evoked EPSCs in ON-SACs from stg mice were ∼30% smaller compared to heterozygous littermates. There was also loss of a transient ON pathway driven GABAergic input to ON-SACs in stg mutants. Direction-selective ganglion cells in the stg mouse showed normal directional tuning, but their surround inhibition and thus spatial tuning was reduced. Our results indicate that TARPɣ2 is required for normal synaptic expression of GluA2, -A3 and -A4 in the inner retina. The presence of residual AMPAR expression in the stargazer mutant suggests that other TARP subunits may compensate in the absence of TARPɣ2.Significance StatementTransmembrane AMPA receptor regulatory proteins (TARPs) are molecules that regulate the targeting and functions of AMPA receptors, which are essential for transmitting signals between neurons in the retina and brain. Here, we identify a specific TARP subunit that plays a role in motion-sensitive circuits of the retina. Our results shed light on how AMPAR auxiliary subunit interactions influence neural signaling in the retina.