Objective Two novel neuropeptides, orexin-A and orexin-B, are identified as endogenous ligands of two orphan G-protein-coupled receptors: orexin 1 and orexin 2 receptors (OX1R and OX2R).This neuropeptide system is involved in a variety of physiological processes, such as sleep/wake regulation, feeding behaviors etc.Whilst most of the mammalian suprachiasmatic nucleus (SCN) circadian clock is photoentrained by photic signals from the retina through the retinohypothalamic tract, little is known about the distribution and function of orexins in retina.The purpose of this study is to investigate how orexins and OXRs are expressed in the rat retina and how orexin-A modulates AMPA receptors in retinal ganglion cells (GCs).Methods Western blot analysis and immunocytochemistry were used to explore the distribution of orexins and OXRs in rat retina, Effects of orexin-A on AMPA receptor-mediated currents were investigated in freshly dissociated GCs by whole cell patch-clamp recording techniques.Results By immunocytochemistry, we show that orexin-A and orexin-B are strongly expressed in horizontal, bipolar, amacrine cells (ACs) and GCs.Moreover, OX1R immunoreactivity is observed in most of GCs and all dopaminergic ACs, as well as in both outer and inner plexiform layers.In contrast, no obvious OX2R immunostaining is detectable in the rat retina.Using patch-clamp whole-cell recording, we first characterized AMPA receptor-mediated currents of GCs.Furthermore, we found that 100 nM orexin-A suppressed AMPA-induced currents in 53 out of 59 OFF-type GCs tested.On average, following the perfusion of 100 nM orexin-A, the AMPA-induced currents were reduced to 62.0 + 2.1% of control (P < 0.0001).In contrast, 100 nM orexin-A increased AMPA-induced currents in 11 out of 14 ON-type GCs to 153.7 ±-8.5 % of control (P < 0.0001).The effects of orexin-A were completely blocked by TCS1102, an antagonist for both OX1R and OX2R (n =7).In most of ON-and OFF-GCs, the effects of orexin-A were eliminated by SB334867, a selective OX1R antagonist.In addition, [Ala11, D-Leu15]-orexin-B, a selective OX2R agonist, did not mimic the actions of orexin-A in 10 of 12 GCs tested.PKC may be involved in the orexin-A effects, as it was eliminated by internal infusion of the PKC inhibitor Bis-Ⅳ (n =7).A detailed analysis of the intracellular signaling pathway mediating this effect is being conducted.Conclusion Orexin-A palys a modulatory role in retinal information processing by differentially modulating AMPA receptor-mediated responses of ON-and OFF-types of GCs.Such modulation is mediated by OX1R and it involves the activation of PKC.