Abstract
Purpose :
There is currently no cure for the vision loss in glaucoma that is characterized by retinal ganglion cell (RGC) loss and irreversible optic neuropathy. Monocarboxylate transporter2 (MCT2) that transports pyruvate, lactate, and ketone bodies, is exclusively found in neurons such as the RGCs. We have previously shown that MCT2 is lost during glaucoma, in advance of RGC loss, and MCT2 overexpression protects RGC number and function. This study was undertaken to test whether MCT2 is necessary for RGC survival and function.
Methods :
To test this hypothesis, we used tamoxifen injection into Thy1-ERT2-cre: MCT2fl/fl mice to conditionally knock out MCT2 from Thy1-positive RGCs. Control mice carried the MCT2 flox’d allele but were Thy1-ERT2-cre-negative. Control and experimental mice were subjected to ocular hypertension using the magnetic microbead model; separate naïve controls from each genotype were also evaluated. Intraocular pressure (IOP) was measured using the TonoLab rebound tonometer. Pattern electroretinogram (PERG) was used to analyze RGC function. Unbiased stereology (Stereo Investigator, Micro Brightfield) was used to count the number of retinal ganglion cells in wholemount retina, and ATP levels in retina were also measured.
Results :
IOP was higher in the ocular hypertension (OHT) groups. MCT2 knockout alone did not impact IOP, nor did it alter baseline PERG amplitude (p=0.663) or latency (p=0.2326). After OHT, PERG amplitude was significantly lower in the MCT2-knockout mice (p=0.0005). MCT2 knockout alone did not change RGC density (p=0.9969). After OHT, RGC density was significantly decreased (p=0.005). There was a trend toward higher ATP production in the OHT+ Tamoxifen group compared to OHT Control; however, the values were not statistically different (p=0.0525).
Conclusions :
RGCs displayed resilience to MCT2 knockout, as shown by no change in PERG in control versus MCT2 knockout retina. Ocular hypertension decreased PERG amplitude and RGC density, and the magnitude of the decrease did not appear to have been increased by MCT2 knockout. These data suggest that RGCs are capable of meeting their immediate metabolic needs through means beyond MCT2.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.