title: Gap junction-mediated death of retinal neurons is connexin and insult specific: a potential target for neuroprotection.
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.
authors.affiliation: 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.
authors.forename: Abram
authors.identifier: http://orcid.org/0000-0002-2200-215X
authors.initials: A
authors.lastname: Akopian
authors.affiliation: Department of Ophthalmology, New York University School of Medicine, New York, New York 10016, and.
authors.forename: Tamas
authors.identifier: http://orcid.org/0000-0002-8112-8633
authors.initials: T
authors.lastname: Atlasz
authors.affiliation: 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.
authors.forename: Feng
authors.initials: F
authors.lastname: Pan
authors.affiliation: Department of Physiology & Neuroscience, New York University School of Medicine, New York, New York 10016.
authors.forename: Sze
authors.initials: S
authors.lastname: Wong
authors.affiliation: Department of Physiology & Neuroscience, New York University School of Medicine, New York, New York 10016.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology, New York University School of Medicine, New York, New York 10016, and.
authors.forename: Béla
authors.initials: B
authors.lastname: Völgyi
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: David L
authors.initials: DL
authors.lastname: Paul
authors.affiliation: 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.
authors.forename: Stewart A
authors.initials: SA
authors.lastname: Bloomfield
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002772:Cholera Toxin / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D017630:Connexins / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005260:Female; D005452:Fluoresceins; D017629:Gap Junctions / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016202:N-Methylaspartate / Q000633:toxicity; D012160:Retina / Q000166:cytology* / Q000293:injuries; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000502:physiology*; D014795:Visual Pathways / Q000187:drug effects / Q000378:metabolism
chemical_list: D017630:Connexins; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D005452:Fluoresceins; D005904:Glial Fibrillary Acidic Protein; C119129:18alpha-glycyrrhetinic acid; C085925:calcein AM; D016202:N-Methylaspartate; D002772:Cholera Toxin; D002795:Choline O-Acetyltransferase; D006034:Glycyrrhetinic Acid
keywords: bystander effect; cell death; connexin; gap junctions; neuroprotection; retina
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