Targeting neuronal gap junctions in mouse retina offers neuroprotection in glaucoma
Abram Akopian, Sandeep Kumar, Hariharasubramanian Ramakrishnan, Kaushambi Roy, Suresh Viswanathan, Stewart A. Bloomfield
Abram Akopian, Sandeep Kumar, Hariharasubramanian Ramakrishnan, Kaushambi Roy, Suresh Viswanathan, Stewart A. Bloomfield
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Research Article Neuroscience Ophthalmology

Targeting neuronal gap junctions in mouse retina offers neuroprotection in glaucoma

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 4

GJ blockade or ablation protects ACs in glaucomatous eyes.

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GJ blockade or ablation protects ACs in glaucomatous eyes. (A–C) Represe...
(A–C) Representative images of vertical sections of CxWT mouse retinas immunostained for GABA and counterstained for DAPI under control conditions and 8 weeks after microbead injections with or without MFA treatment. Scale bar: 50 μm for all panels. Z-stack: 5 sections, 2-μm steps. (D and E) Representative images of vertical sections of Cx36–/– mouse retinas immunostained for GABA and counterstained for DAPI under control conditions and 8 weeks after microbead injections. Z-stack: 5 sections, 2-μm steps. (F–H) Representative images of vertical sections of CxWT mouse retinas immunostained for CR and counterstained for DAPI under control and glaucomatous conditions with or without MFA treatment. Scale bar: 50 μm for all panels. Z-stack: 5 sections, 2-μm steps. (I and J) Representative images of vertical sections of Cx36–/– mouse retinas immunostained for CR and counterstained for DAPI under control conditions and 8 weeks after microbead injections with or without MFA treatment. Z-stack: 5 sections, 2-μm steps. (K) Quantification of the number of GABA-positive ACs in the INL and GCL of retinas from CxWT mice under control and experimental conditions as presented in A–C (n = 12 retinas per group). (L) Quantification of the number of GABA-positive ACs in the INL and GCL of retinas from control and microbead-injected Cx36–/– (n = 10 retinas per group) and Cx36–/– Cx45–/– mice (n = 8 retinas). (M) Quantification of the number of CR-positive cells in the INL and GCL of CxWT mouse retinas under conditions detailed in F–H (n = 10 retinas per group). (N) Quantification of the number of CR-positive cells in the INL and GCL of retinas from control and microbead-injected Cx36–/– (n = 10 retinas) and Cx36–/– Cx45–/– mice (n = 8 retinas). Results are presented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, 1-way ANOVA followed by Tukey’s multiple comparisons test.