Glucocorticoid-induced ocular hypertension alters synaptic plasticity and neurotransmission during the progression of glaucomatous neurodegeneration




Maddineni, Prabhavathi
Kasetti, Ramesh
Zode, Gulab


0000-0002-6928-254X (Maddineni, Prabhavathi)

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Purpose: Elevated intraocular pressure (IOP) is the major risk factor for Primary Open Angle Glaucoma (POAG). The neurodegeneration in POAG extends beyond the eye into the visual centers of the brain (VCB). Unfortunately, the underlying mechanisms responsible for IOP-induced neurodegeneration still remain unclear. We have developed a 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 in VCB contribute to neurodegeneration. 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 the electrical response of VCB was measured by VEP. Expression of synaptic markers in VCB were assessed by immunostaining. Results: Dex-induced OHT led to glaucomatous neurodegeneration in 10-weeks Dex treated mice compared to Veh mice. 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 OHT. Also, we observed an altered synaptic plasticity with decreased expression of both pre and post synaptic markers in the VCB of the 10-weeks Dex treated mouse. Conclusion: These data highlights that GC-induced OHT alters neurotransmission and axonal synaptic plasticity in VCB during the progression of glaucomatous neurodegeneration.