Intrinsically photosensitive retinal ganglion cells are resistant to N-methyl-D-aspartic acid excitotoxicity

PURPOSE: 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.