Continuous Hypoxia Reduces Retinal Ganglion Cell Degeneration in a Mouse Model of Mitochondrial Optic Neuropathy

Abstract

Purpose To test whether continuous hypoxia is neuroprotective to retinal ganglion cells (RGCs) in a mouse model of mitochondrial optic neuropathy. Methods RGC degeneration was assessed in genetically modified mice in which the floxed gene for the complex I subunit NDUFS4 is deleted from RGCs using Vlgut2 -driven Cre recombinase. Beginning at postnatal day 25 (P25), Vglut2-Cre;ndufs4 loxP/loxP mice and control littermates were housed under hypoxia (11% oxygen) or kept under normoxia (21% oxygen). Survival of RGC somas and axons was assessed at P60 and P90 via histological analysis of retinal flatmounts and optic nerve cross-sections, respectively. Retinal tissue was also assessed for gliosis and neuroinflammation using western blot and immunofluorescence. Results Consistent with our previous characterization of this model, at least one-third of RGCs had degenerated by P60 in Vglut2-Cre;ndufs4 loxP/loxP mice remaining under normoxia. However, continuous hypoxia resulted in complete rescue of RGC somas and axons at this time point, with normal axonal myelination observed on electron microscopy. Though only partial, hypoxia-mediated rescue of complex I–deficient RGC somas and axons remained significant at P90. Hypoxia prevented reactive gliosis at P60, but the retinal accumulation of Iba1 + mononuclear phagocytic cells was not substantially reduced. Conclusions Continuous hypoxia achieved dramatic rescue of early RGC degeneration in mice with severe mitochondrial dysfunction. Although complete rescue was not durable to P90, our observations suggest that investigating the mechanisms underlying hypoxia-mediated neuroprotection of RGCs may identify useful therapeutic strategies for optic neuropathies resulting from less profound mitochondrial impairment, such as Leber hereditary optic neuropathy.

Inhibition of high-voltage-activated calcium currents by acute hypoxia in cultured retinal ganglion cells

“…Retinal ganglion cells (RGCs) are the output neurons of the retina that collect, process, and transmit signals to the visual centers of the brain. Changes in electrophysiological characteristics and activity parameters of RGCs induced by sustained and long-lasting hypoxia were previously investigated (Kaur et al, 2008 ; Chidlow et al, 2017 ; Lee et al, 2022 ; Warwick et al, 2022 ). However, there is very limited information about the early effects induced by acute hypoxia in RGCs (Gross et al, 1999 ).…”

Hypoxia-Induced Cardiac Arrest Alters Central Nervous System Concentrations of the GLYT2 Glycine Transporter in Zebrafish (Danio rerio)

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