title: Intrinsically photosensitive retinal ganglion cells are resistant to N-methyl-D-aspartic acid excitotoxicity.
abstract: OBJECTIVE
  Intrinsically photosensitive retinal ganglion cells (ipRGCs) express the photopigment melanopsin (OPN4) and are mainly responsible for non-image-forming visual tasks such as circadian photoentrainment and the pupillary light reflex. Compared to other classes of RGCs, ipRGCs are more resistant to cell death in several experimental models such as ocular hypertension, optic nerve transection, and others. Here, we tested whether ipRGCs are also resistant to N-methyl-D-aspartic acid (NMDA)-induced excitotoxicity.
  
  
  METHODS
  Mice were injected intravitreally with NMDA, and subsequent expression levels of Opn4 and Brn3a mRNA were analyzed with semiquantitative real-time PCR. Cells immunopositive for BRN3A and OPN4 were quantified in retinal flat mounts of NMDA- and PBS-injected eyes. The molecular response of the retina to NMDA treatment was analyzed with real-time PCR and western blotting. Intravitreal injections of wortmannin and AG-490 were used to inhibit phosphatidylinositol 3-kinase (PI3K)/AKT and Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling, respectively.
  
  
  RESULTS
  In contrast to retinal Brn3a expression and BRN3A-containing cells, levels of Opn4 mRNA and the number of OPN4-expressing cells were not reduced after NMDA injection. Survival of ipRGCs after NMDA injection was not strain specific, did not require the presence of photoreceptor cells, and did not depend on PI3K/AKT or JAK/STAT signaling, although both signaling pathways were activated after NMDA treatment.
  
  
  CONCLUSIONS
  Our data support the existence of an efficient survival system for ipRGCs. This system does not depend on PI3K/AKT or JAK/STAT signaling. Identification of the responsible molecular survival mechanisms may provide clues to protect "traditional" ganglion cells in diseases such as glaucoma.
authors.affiliation: Lab of Retinal Cell Biology, Dept Ophthalmology, University of Zurich, Switzerland.
authors.forename: Sw
authors.initials: S
authors.lastname: DeParis
authors.forename: C
authors.initials: C
authors.lastname: Caprara
authors.forename: C
authors.initials: C
authors.lastname: Grimm
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D058449:Intravitreal Injections; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008027:Light; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology*; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012165:Retinal Ganglion Cells / Q000145:classification / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D017299:Rod Opsins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D050819:Transcription Factor Brn-3A / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000528:radiation effects; D020032:Tyrphostins / Q000494:pharmacology; D000077191:Wortmannin; D000099210:Melanopsin
chemical_list: D000730:Androstadienes; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D053612:Janus Kinases; D016202:N-Methylaspartate; D058539:Phosphatidylinositol 3-Kinase; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D017299:Rod Opsins; D050819:Transcription Factor Brn-3A; D020032:Tyrphostins; D000077191:Wortmannin; D000099210:Melanopsin; C494189:Pou4f1 protein, mouse; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide