Early Functional Impairment in Experimental Glaucoma Is Accompanied by Disruption of the GABAergic System and Inceptive Neuroinflammation

Int J Mol Sci. 2021 Jul 15;22(14):7581. doi: 10.3390/ijms22147581.

Abstract

Glaucoma is a leading cause of irreversible blindness worldwide, and increased intraocular pressure (IOP) is a major risk factor. We aimed to determine if early functional and molecular differences in the glaucomatous retina manifest before significant retinal ganglion cell (RGC) loss is apparent. Adenoviral vectors expressing a pathogenic form of myocilin (Ad5.MYOC) were used to induce IOP elevation in C57BL/6 mice. IOP and pattern electroretinograms (pERG) were recorded, and retinas were prepared for RNA sequencing, immunohistochemistry, or to determine RGC loss. Ocular injection of Ad5.MYOC leads to reliable IOP elevation, resulting in significant loss of RGC after nine weeks. A significant decrease in the pERG amplitude was evident in eyes three weeks after IOP elevation. Retinal gene expression analysis revealed increased expression for 291 genes related to complement cascade, inflammation, and antigen presentation in hypertensive eyes. Decreased expression was found for 378 genes associated with the γ-aminobutyric acid (GABA)ergic and glutamatergic systems and axon guidance. These data suggest that early functional changes in RGC might be due to reduced GABAA receptor signaling and neuroinflammation that precedes RGC loss in this glaucoma model. These initial changes may offer new targets for early detection of glaucoma and the development of new interventions.

Keywords: glaucoma; myocilin; neuroinflammation; pattern electroretinography; retinal ganglion cell loss; γ-aminobutyric acid (GABA).

MeSH terms

  • Animals
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism
  • Disease Models, Animal
  • Eye Proteins / genetics
  • Eye Proteins / metabolism
  • Female
  • GABAergic Neurons / metabolism*
  • GABAergic Neurons / pathology
  • Gene Expression Regulation
  • Glaucoma / etiology
  • Glaucoma / metabolism
  • Glaucoma / pathology*
  • Glycoproteins / genetics
  • Glycoproteins / metabolism
  • Inflammation / metabolism
  • Inflammation / pathology
  • Intraocular Pressure
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Retinal Ganglion Cells / metabolism
  • Retinal Ganglion Cells / pathology*
  • gamma-Aminobutyric Acid / metabolism*

Substances

  • Cytoskeletal Proteins
  • Eye Proteins
  • Glycoproteins
  • trabecular meshwork-induced glucocorticoid response protein
  • gamma-Aminobutyric Acid