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Targeting neuronal gap junctions in mouse retina offers neuroprotection in glaucoma
Abram Akopian, … , Suresh Viswanathan, Stewart A. Bloomfield
Abram Akopian, … , Suresh Viswanathan, Stewart A. Bloomfield
Published June 12, 2017
Citation Information: J Clin Invest. 2017;127(7):2647-2661. https://doi.org/10.1172/JCI91948.
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Research Article Neuroscience Ophthalmology

Targeting neuronal gap junctions in mouse retina offers neuroprotection in glaucoma

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Abstract

The progressive death of retinal ganglion cells and resulting visual deficits are hallmarks of glaucoma, but the underlying mechanisms remain unclear. In many neurodegenerative diseases, cell death induced by primary insult is followed by a wave of secondary loss. Gap junctions (GJs), intercellular channels composed of subunit connexins, can play a major role in secondary cell death by forming conduits through which toxic molecules from dying cells pass to and injure coupled neighbors. Here we have shown that pharmacological blockade of GJs or genetic ablation of connexin 36 (Cx36) subunits, which are highly expressed by retinal neurons, markedly reduced loss of neurons and optic nerve axons in a mouse model of glaucoma. Further, functional parameters that are negatively affected in glaucoma, including the electroretinogram, visual evoked potential, visual spatial acuity, and contrast sensitivity, were maintained at control levels when Cx36 was ablated. Neuronal GJs may thus represent potential therapeutic targets to prevent the progressive neurodegeneration and visual impairment associated with glaucoma.

Authors

Abram Akopian, Sandeep Kumar, Hariharasubramanian Ramakrishnan, Kaushambi Roy, Suresh Viswanathan, Stewart A. Bloomfield

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Figure 6

Ablation of neuronal Cx36 protects the optic nerve in experimental glaucoma.

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Ablation of neuronal Cx36 protects the optic nerve in experimental glauc...
(A) Representative cross-sectional images of the glial lamina region of the optic nerve from control CxWT animals immunostained for GFAP, SMI32, and DAPI. Magnified images of the area outlined in the left panel show the immunolabeling pattern for GFAP and SMI32. Scale bars: 100 μm for all panels in the left column and 25 μm for panels in all other columns. (B) Representative cross-sectional images of the glial lamina region of the optic nerve from CxWT animals 8 weeks after initial microbead injection. Conventions are the same as in A. (C) Representative cross-sectional images of the glial lamina region of the optic nerve from Cx36–/– mice under control conditions. Conventions are the same as in A. (D) Representative cross-sectional images of the glial lamina region of the optic nerve from Cx36–/– animals 8 weeks after initial microbead injection. Conventions are the same as in A. (E) Quantification of GFAP labeling in the cross sections of optic nerves of CxWT mice under control and glaucomatous conditions (n = 5 optic nerves per group). (F) Quantification of GFAP labeling in the cross sections of optic nerves of Cx36–/– mice under control and glaucomatous conditions (n = 5 optic nerves per group). (G) Quantification of SMI32 labeling in the cross sections of optic nerves of CxWT mice under control and glaucomatous conditions (n = 5 optic nerves per group). (H) Quantification of SMI32 labeling in the cross sections of Cx36–/– mice under control and glaucomatous conditions (n = 5 optic nerves per group). Z-stack: 5 sections, 0.7-μm steps for all images. Data are presented as mean ± SEM. *P < 0.05, ***P < 0.001, Student’s t test.
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