Neurobiology of Glaucoma

The neurobiology of retinal cell death in glaucoma is not well understood, partly because of its complexity. It involves a variety of cell types, and is affected by a variety of processes including systemic and environmental factors.  Because of this complexity, it is necessary to study the condition in whole animals to decipher disease mechanisms and to test treatments.  The mouse system is the most powerful experimental mammalian system for studying complex diseases like glaucoma.  For this reason, we pioneered the use of mouse models for glaucoma research, providing new models and tools for following disease phenotypes, and characterizing pertinent ocular anatomy, development and physiology.  These efforts have proved very worthwhile and clearly demonstrate that mice provide valuable, powerful and relevant models for studying glaucoma. Mice have rapidly become the most widely used animal models for studying glaucoma. 

On this page:

Mouse Models

Different Cell Types are Important

DBA/2J Mice

Identifying Early Stages of Glaucoma

Complement and Endothelin Systems

Axon Degeneration and Glaucoma

Mouse Models

We have developed various inherited mouse models of glaucoma to study neurodegenerative changes in both the retina and optic nerve.  Additionally and where appropriate, we use various induced models.  Since glaucoma is heterogeneous and complex, it is ultimately important to study disease processes using a variety of models with different genetic make-ups. The relative importance of specific disease processes will differ between models as is true between different glaucoma patients. For this reason we continue to develop new models. As we learn more about human glaucoma, it will become increasingly possible to study mice with mutations in known human glaucoma genes. We use mouse models of different forms of glaucoma including open-angle, closed angle, developmental and secondary glaucoma. Some of these mice have mutation in genes that cause human glaucoma.

Different Cell Types are Important

Glaucoma is characterized by the death of retinal ganglion cells (RGCs) and degeneration of the optic nerve.  Although cell death is largely specific to RGCs in the retina, a variety of cell types are believed to be important in glaucomatous pathology and/or determining disease outcome.  In addition to RGCs, important cell types to study are astrocytes, microglia, vascular endothelial cells and others.  We are studying disease processes in these different cell types using both genomics and genetics approaches.  We are developing mice that will allow us to test the importance for glaucoma of specific biological pathways in individual cell types.  We are generating important resources for these experiments that will be made available to the research community.

DBA/2J mice

Our group contributed heavily to the development of the DBA/2J mouse strain as an inherited model of glaucoma, and it remains a central model for glaucoma research. The glaucoma of DBA/2J mice has hallmarks of human glaucoma including age-related intraocular pressure elevation, regional loss of retinal ganglion cells, and optic nerve head remodeling or excavation. DBA/2J mice provide a tractable model for dissecting pathways of cell death in inherited glaucoma and for investigating neuroprotective strategies. The inherited nature of the DBA/2J disease, marked by a progressive, relatively mild onset of pressure insult, is an important feature of this model.

Identifying Early Stages of Glaucoma

We have used DBA/2J mice to determine mechanisms of glaucomatous RGC loss. Recently, we used a powerful genomics method, gene expression profiling, along with sophisticated computational clustering methods to identify early molecular stages of disease. We have developed software and an online interface (Glaucoma Discovery Platform) to allow easy access and querying of these data by clinicians and researchers worldwide.  This software is also available as a generic download to facilitate the analysis and distribution of other data sets (Datgan). The methods that we used to identify these early stages are likely to prove effective for understanding early stages of other complex diseases including Alzheimer’s disease.

Complement and Endothelin Systems

Analysis of these early stages revealed that induction of both the complement and endothelin systems occurs very early in glaucoma. In fact these inductions are among the earliest process to occur.  The complement system is induced in both the optic nerve and retina. In the retina, it appears to contribute to the loss of connections between neural cells known as synapses.  Synapse loss will damage RGCs and impede vision. In the optic nerve, it is likely to contribute to axon damage. The endothelin system is best known for its potent effects that constrict blood vessels.   Vascular constriction will impede blood flow and is likely to decrease availability of nutrients and oxygen and this would stress retinal ganglion cells.  We have demonstrated that separately inhibiting these pathways is highly protective against glaucomatous neurodegeneration.  Ongoing experiments are investigating the role of the complement and endothelin systems in early glaucoma. As both of these systems are activated in human glaucoma, this is an important step towards developing improved therapies for human glaucoma.

Axon Degeneration and Glaucoma

Using DBA/2J mice, we found that the death of RGC cell bodies (individually known as soma) completely depends on the actions of a molecule know as BAX.  Mutating BAX completely prevents RGC cell death in this glaucoma. In contrast, BAX is not required for the degeneration of RGC axons, the part of RGCs that acts like an electrical wire and connects them to the brain.  These experiments show that different parts of a RGC degenerate through different processes, and that to be effective treatments will have protect both the soma and axon.  We subsequently demonstrated that the axons of RGCs are directly insulted in a small region of the optic nerve known as the optic nerve head.  This region is rich in astrocytes, which may be important in modulating glaucomatous damage.  We also found that RGC loss is prevented in many eyes by the Wallerian degeneration slow (Wlds) gene, which is known to protect from axon degeneration processes.  Future efforts will focus on understanding the axonal degeneration pathways. These studies will provide new insights into RGC death in glaucoma and will identify potential therapeutic targets.