A decrease in phosphorylation of cAMP-response element-binding protein (CREBP) promotes retinal degeneration

Area of Science:

• Neuroscience
• Ophthalmology
• Cell Biology

Background:

• Excitotoxicity from N-Methyl-d-aspartate (NMDA) or kainic acid (KA) leads to irreversible retinal ganglion cell (RGC) loss.
• NMDA excitotoxicity increases CREBP phosphorylation, while KA excitotoxicity in the central nervous system decreases it, suggesting differential roles.
• The specific role of CREBP in KA-induced RGC death remains uninvestigated.

Purpose of the Study:

• To investigate if KA-induced excitotoxicity decreases Ser(133)-CREBP phosphorylation in the retina.
• To elucidate the role of CREBP in KA-mediated RGC death.

Main Methods:

• KA was intravitreally injected into CD-1 mice to induce excitotoxicity.
• CREBP levels and phosphorylation were assessed using immunohistochemistry, western blot, and electrophoretic mobility gel shift assays (EMSAs).
• The effect of CNQX, a non-NMDA glutamate receptor antagonist, was evaluated.

Main Results:

• KA injection decreased nuclear Ser(133)-CREBP localization in the ganglion cell layer (GCL) and inner nuclear layer (INL).
• Reduced Ser(133)-CREBP levels correlated with apoptotic RGC and amacrine cell death.
• CNQX treatment prevented KA-induced Ser(133)-CREBP decrease and inhibited cell loss.

Conclusions:

• KA promotes retinal degeneration by reducing Ser(133)-CREBP phosphorylation in the retina.
• This study identifies a novel mechanism for KA-induced RGC death involving CREBP dephosphorylation.
• Targeting CREBP phosphorylation may offer a therapeutic strategy against KA-induced retinal damage.