title: Ectopic vesicular glutamate release at the optic nerve head and axon loss in mouse experimental glaucoma.
abstract: Although clinical and experimental observations indicate that the optic nerve head (ONH) is a major site of axon degeneration in glaucoma, the mechanisms by which local retinal ganglion cell (RGC) axons are injured and damage spreads among axons remain poorly defined. Using a laser-induced ocular hypertension (LIOH) mouse model of glaucoma, we found that within 48 h of intraocular pressure elevation, RGC axon segments within the ONH exhibited ectopic accumulation and colocalization of multiple components of the glutamatergic presynaptic machinery including the vesicular glutamate transporter VGLUT2, several synaptic vesicle marker proteins, glutamate, the soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex and active zone cytomatrix components, as well as ultrastructurally identified, synaptophysin-containing vesicles. Ectopic vesicle exocytosis and glutamate release were detected in acute preparations of the LIOH ONH. Immunolocalization and analysis using the ionotropic receptor channel-permeant cation agmatine indicated that ONH axon segments and glia expressed glutamate receptors, and these receptors were more active after LIOH compared with controls. Pharmacological antagonism of glutamate receptors and neuronal activity resulted in increased RGC axon sparing in vivo. Furthermore, in vivo RGC-specific genetic disruption of the vesicular glutamate transporter VGLUT2 or the obligatory NMDA receptor subunit NR1 promoted axon survival in experimental glaucoma. As the inhibition of ectopic glutamate vesicular release or glutamate receptivity can independently modify the severity of RGC axon loss, synaptic release mechanisms may provide useful therapeutic entry points into glaucomatous axon degeneration.
authors.affiliation: Neuroscience Graduate Program, Departments of Ophthalmology and Physiology, University of California, San Francisco, San Francisco, California 94143, USA.
authors.forename: Christine T
authors.initials: CT
authors.lastname: Fu
authors.forename: David W
authors.initials: DW
authors.lastname: Sretavan
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000648:ultrastructure; D004195:Disease Models, Animal; D005089:Exocytosis / Q000502:physiology*; D005901:Glaucoma / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D007429:Intraocular Pressure; D051379:Mice; D009898:Optic Disk / Q000378:metabolism* / Q000648:ultrastructure; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000648:ultrastructure; D022142:Secretory Vesicles / Q000378:metabolism* / Q000648:ultrastructure; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure; D016708:Synaptophysin / Q000378:metabolism; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism
chemical_list: D016708:Synaptophysin; D050599:Vesicular Glutamate Transport Protein 2; D018698:Glutamic Acid