Abstract
Purpose :
Primary Open Angle Glaucoma (POAG), the most common form of glaucoma, is characterized by progressive loss of retinal ganglion cells (RGCs) and their axons. Elevated intraocular pressure (IOP) is the major risk factor for POAG. The neurodegeneration in POAG extends beyond the eye into the visual centers of the brain (VCB). Unfortunately, the underlying pathological mechanisms responsible for IOP-induced glaucomatous neurodegeneration still remain unclear. To this end, we have developed a novel glucocorticoid (GC)-induced mouse model of glaucoma, and determined the role of GC-induced ocular hypertension (OHT) on synaptic dysfunction, and how alterations in synaptic plasticity contribute to glaucomatous neurodegeneration in the VCB.
Methods :
C57BL/6J mice were injected with either Dexamethasone (Dex) or Vehicle (Veh) via periocular-route, once a week for 10-weeks. IOP was measured every week and glaucomatous neurodegeneration was examined using pattern ERG (pERG), whole mount retina staining with RBPMS antibody and PPD staining for optic nerve (ON) degeneration. The electrical response of the brain’s primary visual cortex was measured using visually evoked potential (VEP). Expression of synaptic markers in the VC of the brain were assessed by immunostaining.
Results :
Dex-induced sustained OHT led to glaucomatous neurodegeneration in 10-weeks Dex treated mice compared to Veh treated mice. Glaucomatous neurodegeneration was associated with significant functional and structural loss of RGCs as evident from reduced pERG amplitudes (10µV v/s 25µV), with ~33% RGC loss and ~62% axonal loss. We observed RGC hyper excitability during the early stages of axonal damage with significantly increased VEP amplitudes with decreased latencies in 5-weeks Dex treated mice (32μV; 73ms) compared to Veh mice (26μV; 79ms). Interestingly, we observed complete collapse of neuronal excitability, with decreased VEP amplitudes and increased latencies in 10-weeks Dex treated mice (12μV; 132ms) due to chronic IOP elevation. Also, we observed an altered synaptic plasticity with decreased expression of both pre and post synaptic markers (VGLUT-2 and PSD-95 respectively) in the VC of the 10-weeks Dex treated mouse brain.
Conclusions :
These data highlights that OHT alters neurotransmission and axonal synaptic plasticity in the VC of the brain during the progression of glaucomatous neurodegeneration.
This is a 2021 ARVO Annual Meeting abstract.