Damage to Rod Circuitry Underlies Ganglion Cell Functional Changes in Glaucoma

Baylor College Of Medicine, Houston TX

Investigators

Linked publications & trials

Abstract

? DESCRIPTION (provided by applicant): Glaucoma is the second leading cause of blindness worldwide and current forms of treatment only halt disease progress. For this reason, identifying and treating glaucoma patients prior to significant visual damage represents the best way to improve patient quality of life. Increased intraocular pressure (IOP) is the biggest risk factor fo glaucoma and focus of current treatment. A recently developed experimental model of glaucoma in the mouse raises IOP by injecting beads into the eye to block fluid flow. The bulk of glaucoma studies have focused on retinal ganglion cell (RGC) death, but recent investigation in this experimental model found that functional deficits in RGCs are observable prior to cell death. RGC function is derived from the convergence of unique upstream circuitry, which can broadly be broken down into rod dominated circuitry for encoding dim light and cone dominated circuitry for encoding bright light. The rod pathway can be further broken down into specific pathways. Loss of night and peripheral vision along with selective death of large RGCs early in glaucoma pathogenesis indicates dysfunction in the rod dominated circuitry. No study has been carried out to directly determine if these circuits are more susceptible to glaucomatous damage. In order to answer this question a multielectrode array (MEA) will be used to record activity from many RGCs while IOP is modulated. Using subsequent analysis procedures RGC functional properties can be extracted from RGC activity. Pairing the IOP-induced damage with circuit isolation allows determination of the dependence of IOP-induced damage on rod and cone pathways. Experimentally two strategies can be used to isolate specific circuitry contribution to RGC properties. The first approach can broadly isolate the rod and cone circuitry by using dim and bright light, respectively. The second approach uses Bhlhb4(-/-) mice which have disrupted rod bipolar cells causing deficiency in the most sensitive rod pathway, the primary pathway. Using these approaches we will determine if glaucoma, via elevated IOP, depends on the rod circuits or subcircuits to alter RGC properties. The findings from this study can be directly translated into novel diagnostic tests for earlier disease detection.