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Yin Shen, Yumeng Shen, Xue Luo, Shiliang Liu; NMDA caused rod bipolar cell dysfunction before ganglion cell loss in a mouse model of experimental glaucoma. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3718.
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© ARVO (1962-2015); The Authors (2016-present)
Glaucoma is the second leading cause of blindness worldwide due to the irreversible degeneration of retinal ganglion cells (RGCs). It has been reported that the inner retinal dysfunction might happen before cell loss in glaucoma, whereas, the effects of inner retina and the underlying mechanisms were unclear. In this study, we tried to identify the changes of bipolar cells (BCs), excitatory presynaptic input of RGCs, in glaucoma, and explore the possible signal pathway.
Intravitreal injection of NMDA to induce acute glaucoma in C57/BL6 mouse, laterally injection of PBS as control. Then western blot, immunohistochemistry staining, electroretinogram (ERG) recording, whole-cell patch clamp recording, Co-IP were performed to identify the changes of BCs.
NMDA 0.05mM injection for 0.5h decreased nearly half of the amplitude of b-wave in ERG responses, whereas, didn't affected the Brn3a-positive RGCs, indicating a dysfunction of BCs before RGCs. The expression level of PCP2 which expression in all BCs was not changed, while, the protein kinase C alpha (PKCα), a functional protein of rod BCs (RBCs), was significantly reduced under NMDA application. Consistently, CPPG induced currents of RBCs was dramatically declined, but not ON and OFF cone BCs (CBCs) in NMDA group. Furthermore, incubation of PMA, PKCα activator, partially increased the CPPG induced currents. Application of PMA also significantly rescue the reduction of PKCα in NMDA model. PKCα trafficking is known to be dependent on NR2B and PICK1. Co-IP of NR2B, PICK1 and PKCα confirmed that these three proteins combined directly with each other. Consistently, NMDA induced a gradually increase of total NR2B and phosphorylation NR2B (p-NR2B). Meanwhile, NMDA induced reduction of PKCα was blocked in PICK1 knouk out (PICK-/-) mice indicating the involvement of PICK1. In addition, similar reduction of PKCα was also found in other glaucoma model such as acute ocular hypertension (AOH) model and optic nerve crush (ONC) model indicating an universal mechanism in retinal degeneration.
Our studies firstly revealed a RBCs dysfunction in different glaucoma models, which caused by PKCα reduction. Furthermore, we explored the reduction was modulated via interaction with NR2B and PICK1. This results provided a novel insight in the degeneration of inner retina other than RGCs.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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