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Tsung-Han Chou, Hong Yu, Rajeshwari D. Koilkonda, Angelina Lazo, Vittorio Porciatti; Autoregulatory dynamics of the PERG in mice with induced and rescued mitochondrial dysfunction. Invest. Ophthalmol. Vis. Sci. 2022;63(7):762 – F0414.
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© ARVO (1962-2015); The Authors (2016-present)
Flickering light around 10 Hz induces rapid dilation of retinal vessels in the inner retina as well as progressive reduction (adaptation) of Pattern Electroretinogram (PERG) amplitude, indicating neuro-vascular-metabolic autoregulation. We measured flicker-PERG adaptation in control mice, in mice with induced mitochondrial dysfunction mimicking Leber Hereditary Optic Neuropathy (LHON) and in mice where induced LHON was rescued with gene-therapy.
3-month-old DBA/1J mice were randomly split into three groups and received two intravitreal AAV injections at two-day intervals. The first group (Control, N=17) was injected with AAV/mcherry + AAV/mcherry (4.52 E8 vg/eye); the second group (LHON, N=23) with AAV/mutant ND4 (4.32 E9 vg/eye) + AAV/mcherry (4.52 E8 vg/eye); the third goup (LHON rescue, N=27) with AAV/mutant ND4 (4.32 E9 vg/eye) + AAV/wild-type ND4 (4.4 E8 vg/eye). A group of uninjected mice (naïve control, n=101) was also tested for comparison. In all mice, PERG was recorded from both eyes with superimposed 101 Hz flicker (baseline) and then with 11 Hz flicker (test) and the test minus baseline amplitude was considered as measure of flicker PERG adaptation. Group comparisons were performed using Generalized Estimating Equations (GEE) analysis accounting for the inclusion of both eyes.
In naïve and control groups, the mean PERG adaptation was -4.1 µV (SE=0.42) and -3.2 µV (SE=0.94), respectively; in the LHON group was 0.84 µV (SE=0.89) and in the LHON rescued group was - 2.6 µV (SE=0.94). Multiple comparisons revealed significant (P<0.05) differences between control groups and LHON group and between rescued LHON and LHON group but not between control groups and rescued LHON group.
Mitochondrial dysfunction in a mouse model of LHON abolishes the flicker-induced PERG adaptation normally present in control mice. Gene-therapy to rescue mitochondrial function restores, at least in part, PERG adaptation. Flicker-induced PERG adaptation may represent a physiological tool to investigate altered metabolic autoregulation of retinal ganglion cells in optic neuropathies.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.
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