title: Increased mitochondrial fission and volume density by blocking glutamate excitotoxicity protect glaucomatous optic nerve head astrocytes.
abstract: Abnormal structure and function of astrocytes have been observed within the lamina cribrosa region of the optic nerve head (ONH) in glaucomatous neurodegeneration. Glutamate excitotoxicity-mediated mitochondrial alteration has been implicated in experimental glaucoma. However, the relationships among glutamate excitotoxicity, mitochondrial alteration and ONH astrocytes in the pathogenesis of glaucoma remain unknown. We found that functional N-methyl-d-aspartate (NMDA) receptors (NRs) are present in human ONH astrocytes and that glaucomatous human ONH astrocytes have increased expression levels of NRs and the glutamate aspartate transporter. Glaucomatous human ONH astrocytes exhibit mitochondrial fission that is linked to increased expression of dynamin-related protein 1 and its phosphorylation at Serine 616. In BAC ALDH1L1 eGFP or Thy1-CFP transgenic mice, NMDA treatment induced axon loss as well as hypertrophic morphology and mitochondrial fission in astrocytes of the glial lamina. In human ONH astrocytes, NMDA treatment in vitro triggered mitochondrial fission by decreasing mitochondrial length and number, thereby reducing mitochondrial volume density. However, blocking excitotoxicity by memantine (MEM) prevented these alterations by increasing mitochondrial length, number and volume density. In glaucomatous DBA/2J (D2) mice, blocking excitotoxicity by MEM inhibited the morphological alteration as well as increased mitochondrial number and volume density in astrocytes of the glial lamina. However, blocking excitotoxicity decreased autophagosome/autolysosome volume density in both astrocytes and axons in the glial lamina of glaucomatous D2 mice. These findings provide evidence that blocking excitotoxicity prevents ONH astrocyte dysfunction in glaucomatous neurodegeneration by increasing mitochondrial fission, increasing mitochondrial volume density and length, and decreasing autophagosome/autolysosome formation. GLIA 2015;63:736-753.
authors.affiliation: Department of Ophthalmology, Laboratory for Optic Nerve Biology, Hamilton Glaucoma Center, University of California San Diego, La Jolla, California.
authors.forename: Won-Kyu
authors.initials: WK
authors.lastname: Ju
authors.forename: Keun-Young
authors.initials: KY
authors.lastname: Kim
authors.forename: You Hyun
authors.initials: YH
authors.lastname: Noh
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hoshijima
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Lukas
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ellisman
authors.forename: Robert N
authors.initials: RN
authors.lastname: Weinreb
authors.forename: Guy A
authors.initials: GA
authors.lastname: Perkins
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000444:Aldehyde Dehydrogenase / Q000235:genetics; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D002452:Cell Count; D002478:Cells, Cultured; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005901:Glaucoma / Q000473:pathology*; D018698:Glutamic Acid / Q000494:pharmacology*; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects; D008559:Memantine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D063154:Mitochondrial Dynamics / Q000187:drug effects*; D016202:N-Methylaspartate / Q000494:pharmacology; D009898:Optic Disk / Q000473:pathology*; D000587:Oxidoreductases Acting on CH-NH Group Donors; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000187:drug effects; D000099295:Formyltetrahydrofolate Dehydrogenase
chemical_list: D000444:Aldehyde Dehydrogenase; D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid; D008559:Memantine; D016202:N-Methylaspartate; D000587:Oxidoreductases Acting on CH-NH Group Donors; D000099295:Formyltetrahydrofolate Dehydrogenase
keywords: excitotoxicity; glaucoma; mitochondrial fission; optic nerve head astrocyte