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J Neurosci. 2014 Aug 6;34(32):10582-91. doi: 10.1523/JNEUROSCI.1912-14.2014.

Gap junction-mediated death of retinal neurons is connexin and insult specific: a potential target for neuroprotection.

Author information

1
Department of Biological and Vision Sciences, State University of New York College of Optometry, New York, New York 10036, Department of Physiology & Neuroscience, New York University School of Medicine, New York, New York 10016.
2
Department of Ophthalmology, New York University School of Medicine, New York, New York 10016, and.
3
Department of Physiology & Neuroscience, New York University School of Medicine, New York, New York 10016.
4
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115.
5
Department of Biological and Vision Sciences, State University of New York College of Optometry, New York, New York 10036, Department of Physiology & Neuroscience, New York University School of Medicine, New York, New York 10016, Department of Ophthalmology, New York University School of Medicine, New York, New York 10016, and sbloomfield@sunyopt.edu.

Abstract

Secondary cell death via gap junctions (GJs) plays a role in the propagation of neuronal loss under a number of degenerative disorders. Here, we examined the role of GJs in neuronal death in the retina, which has arguably the most diverse expression of GJs in the CNS. Initially, we induced apoptotic death by injecting single retinal ganglion cells and glia with cytochrome C and found that this resulted in the loss of neighboring cells to which they were coupled via GJs. We next found that pharmacological blockade of GJs eradicated nearly all amacrine cell loss and reduced retinal ganglion cell loss by ∼70% after induction of either excitotoxic or ischemic insult conditions. These data indicate that the GJ-mediated secondary cell death was responsible for the death of most cells. Whereas genetic deletion of the GJ subunit Cx36 increased cell survivability by ∼50% under excitotoxic condition, cell loss in Cx45 knock-out mouse retinas was similar to that seen in wild-type mice. In contrast, ablation of Cx45 reduced neuronal loss by ∼50% under ischemic insult, but ablation of Cx36 offered no protection. Immunolabeling of the connexins showed differential changes in protein expression consistent with their differing roles in propagating death signals under the two insults. These data indicate that secondary cell death is mediated by different cohorts of GJs dependent on the connexins they express and the type of initial insult. Our results suggest that targeting specific connexins offers a novel therapeutic strategy to reduce progressive cell loss under different neurodegenerative conditions.

KEYWORDS:

bystander effect; cell death; connexin; gap junctions; neuroprotection; retina

PMID:
25100592
PMCID:
PMC4200109
DOI:
10.1523/JNEUROSCI.1912-14.2014
[Indexed for MEDLINE]
Free PMC Article

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