Selective Neuronal Damage in Experimental Glaucoma

Glaucoma is a very common cause of severe visual impairment among elderly people. The elevated intra-ocular pressure common to most glaucomas is caused by increased resistance in the trabecular meshwork. Chronically elevated intra-ocular pressure is due to the impaired reabsorption of the aqueous humor within the eye. Studies have shown that the abnormally elevated intra-ocular pressure induces cellular damage in the neurons of the retina that are responsible for conveying the visual stimuli to the brain. It appears that certain types of neurons (ganglion cells) in the retina are particularly sensitive to the degenerative process, whereas other may be spared. Interestingly, it has been demonstrated that comparable patterns of selective neuronal vulnerability occur in other age-related disorders, in particular in the course of senile dementia of the Alzheimer type (Alzheimer’s disease). In this disease, not all neurons in the brain are affected, but certain subpopulations of cells, especially in the cerebral cortex, are exquisitely sensitive to the pathologic process. Thus, certain neurons that connect different regions of the cerebral cortex are dramatically vulnerable, whereas neurons forming local circuits are resistant. Neurons can therefore be distinguished in terms of resistance and vulnerability to a given disease by several criteria including their morphology, connectivity, and by neurochemical constituents. We have used this approach to define a profile of cellular vulnerability to the degenerative process in Alzheimer’s disease. Similar patterns of restricted neuronal alterations have been described in pathological assessments of glaucoma in postmortem human samples and experimental animals. In the present proposal we will use a similar approach to determine the characteristics of the neurons with increased risk of degeneration in glaucoma using an animal model. Specifically, macaque monkeys with experimentally-induced unilateral glaucomatous lesions (through destruction of the corneoscleral angle by laser photocoagulation) will be used to study neuron specific changes in the retina and several relay along the visual pathways.

Hypothesis

In view of the restricted and selective neurodegenerative changes that occur in Alzheimer’s disease. we postulate that 1) Neuron-type selective pathology comparable to that seen in Alzheimer’s disease occurs in glaucoma and affects projection neurons in the retina (ganglion cells) and along the visual pathways; 2) These neurons have particular biochemical characteristics that can be determined using specific anatomical methods including intracellular visualization of structural proteins and excitatory neurotransmitter receptors; 3) The vulnerable neurons exhibit specific regional distribution patterns within the visual pathways; and 4) Depending on the stage of the glaucomatous lesions, neuronal changes occur with increasing degrees of severity in visual relays outside the retina, including the visual cortex.

Specific Aims

The present proposal is specifically designed to investigate cell population-specific patterns of vulnerability associated with the development of experimental glaucoma in macaque monkeys. We will follow an experimental paradigm similar to that used in our previous normative and neuropathologic studies of the monkey and human cerebral cortex to quantify the degree to which biochemically and morphologically identifiable sets of neurons are affected in glaucoma at different levels of the visual pathways. These data will also provide quantitative normative information on the distribution of chemically identified neurons in the primate visual system. Specifically, we will perform the following analyses: 1) Quantify the degree of vulnerability of subtypes of retinal neurons identified by their content of several cellular markers 2) Quantify the repercussion of retinal cell pathology in the retino recipient zones of subcortical relay center in the thalamus and brainstem, as well as in the visual cortex, using the same neuronal markers to identify particular neuronal subsets; 3) The possible role of excitatory neurotransmission in the induction of the cell degenerative changes will be particularly investigated using markers for excitatory neurotransmitter receptors; 4) In order to analyze the time course of glaucomatous changes at several levels within the visual pathways, analyses will be performed not only in monkeys that had elevated intraocular pressure and objective signs of optic nerve damage for an extended period, but also in animals with no or early stages of such damage.

Long-Term Goals

These studies will allow us to determine whether comparable process of neuronal degeneration to that observed in Alzheimer’s disease occurs in glaucoma and whether vulnerable neurons share biochemical features in both disorders. They will also provide information on the degree to which changes at the level of the retina is reflected in different relays along the visual pathways, including the visual cortex, and indicate how the disease changes. Future extensions of the proposed experiments include the combination of chemical identification of select nerve cell populations with tracing of particular connections using transported tracers, refined analysis of neurotransmitter systems at the ultrastructural level, and evaluation of therapeutic interventions on neuronal characteristics in glaucomatous animals. Precise knowledge of the cellular elements of the visual circuits that are affected in glaucoma may ultimately enable correlations between distribution of cellular pathologic changes, neurochemical characteristics related to increased cellular vulnerability and compromised neuronal populations. Such correlations will be useful for the development of therapeutic strategies to prevent or protect neurons against the specific degenerative events that occur during the progression of glaucoma.