Glaucoma is a leading cause of blindness worldwide, which is caused by the degeneration of retinal ganglion cells (RGCs). An elevated intraocular pressure (IOP) is widely recognized as one of the major risk factors for glaucoma. We have reported that purinergic P2Y₁ receptor is essential for IOP reduction and P2Y₁ receptor knockout (P2Y₁KO) mice show hypertensive glaucoma-like phenotype. We already reported that P2Y₁ receptor is located in ciliary body(CB) and trabecular meshwork (TM), and controls production and outflow of aqueous humor, respectively. We also found that ocular hypertension itself did not solely cause RGC degeneration at young ages, so we hypothesized IOP-independent pathogenic mechanism. Immunohistochemical analysis revealed that P2Y₁ receptors were expressed in Müller cells in the retina in addition to CB and TM. To test the role of P2Y₁ receptors in Müller cells for RGC damages, we made Mlc1-tTS::P2ry1^tetO/tetO mice (Müller cell-specific P2Y₁ receptor conditional knockout mice; MC-cKO). We measured the IOP of control (P2ry1^tetO/tetO) and MC-cKO mice and found no difference between them. Next, RGC damage was compared by counting the number of Rbpms-positive cells. Howeve, MC-cKO mice at 12 months old showed significantly higher number of RGCs loss than that in age-matched control mice. Accompanied this, the number of apoptotic cells significantly increased in the MC-cKO mice. Taken together, our results demonstrated that the lack of P2Y₁ receptors in Müller cells promotes RGC loss without IOP elevation, suggesting an importance of Müller cells for pathogenesis of glaucoma. (1303/1350 words)