A role of PSA-NCAM in the survival of retinal ganglion cells (RGCs) after kainic acid damage

Background: Neural cell adhesion molecule (NCAM) belongs to the immunoglobulin superfamily of adhesion molecules. Polysialic acid (PSA) is attached to NCAM post-translationally. PSA residues are considered to reduce the adhesive properties of NCAM and play an important role in the regulation of cell interactions. PSA-NCAM is largely expressed in the mature retina by glial cells adjacent to retinal ganglion cells (RGCs) but its functions remain unclear. The objective of this study was to explore the role of PSA-NCAM with respect to RGC survival following kainic acid (KA)-induced excitotoxicity.

Methods: Experiments were performed on C57BL/6NTac male mice. KA was injected intravitreally to induce RGC damage. RGCs were visualized using an anti-Brn3a antibody. Endoneuraminidase N (NA) was administrated intravitreally to cleave PSA chains from NCAM.

Results: KA induced an 80% reduction in the density of RGCs that was accompanied by a decrease in PSA-NCAM in the RGC layer. KA treatment induced a pronounced increase in the level of matrix metalloproteinase-9 (MMP-9) in the inner layers of the retina. Inhibition of MMP-9 reduced both RGC death and PSA-NCAM shedding in the retina. PSA-NCAM cleavage induced by NA abolished the protective action of the MMP-9 inhibitor and decreased RGC survival following KA-treatment.

Conclusions: A decrease in retinal PSA-NCAM levels following KA administration is due to the induction of active MMP-9, which removes extracellular PSA-NCAM from the surface of astroglial and Müller cells. The MMP-9 induced shedding of PSA-NCAM enhances KA-induced toxicity and at least in part contributes to the observed loss of RGCs following excitotoxic damage.