Early diabetes (4 weeks of hyperglycemia) decreased the frequency of inhibitory signals to retinal ganglion cells.
A reduction in the frequency of GABAergic miniature inhibitory postsynaptic currents was observed in retinal ganglion cells without changes in their amplitude.
Topical glucagon-like peptide-1 eyedrops for 2 weeks countered the decrease in inhibitory current frequency and enhanced retinal ganglion cell survival.
The protective effects of glucagon-like peptide-1 were negated by specific receptor antagonists, indicating receptor involvement.
Glucagon-like peptide-1 increased the frequency of inhibitory signals in both ON- and OFF-type retinal ganglion cells.
Photoresponses of ON-type retinal ganglion cells were functionally augmented by glucagon-like peptide-1.
Diabetic rats showed improved visual acuity and contrast sensitivity after glucagon-like peptide-1 administration.
Simplified
JOURNAL/nrgr/04.03/01300535-202602000-00048/figure1/v/2025-05-05T160104Z/r/image-tiff is a prominent cause of blindness in adults, with early retinal ganglion cell loss contributing to visual dysfunction or blindness. In the brain, defects in γ-aminobutyric acid synaptic transmission are associated with pathophysiological and neurodegenerative disorders, whereas glucagon-like peptide-1 has demonstrated neuroprotective effects. However, it is not yet clear whether diabetes causes alterations in inhibitory input to retinal ganglion cells and whether and how glucagon-like peptide-1 protects against neurodegeneration in the diabetic retina through regulating inhibitory synaptic transmission to retinal ganglion cells. In the present study, we used the patch-clamp technique to record γ-aminobutyric acid subtype A receptor-mediated miniature inhibitory postsynaptic currents in retinal ganglion cells from streptozotocin-induced diabetes model rats. We found that early diabetes (4 weeks of hyperglycemia) decreased the frequency of GABAergic miniature inhibitory postsynaptic currents in retinal ganglion cells without altering their amplitude, suggesting a reduction in the spontaneous release of γ-aminobutyric acid to retinal ganglion cells. Topical administration of glucagon-like peptide-1 eyedrops over a period of 2 weeks effectively countered the hyperglycemia-induced downregulation of GABAergic mIPSC frequency, subsequently enhancing the survival of retinal ganglion cells. Concurrently, the protective effects of glucagon-like peptide-1 on retinal ganglion cells in diabetic rats were eliminated by topical administration of exendin-9-39, a specific glucagon-like peptide-1 receptor antagonist, or SR95531, a specific antagonist of the γ-aminobutyric acid subtype A receptor. Furthermore, extracellular perfusion of glucagon-like peptide-1 was found to elevate the frequencies of GABAergic miniature inhibitory postsynaptic currents in both ON- and OFF-type retinal ganglion cells. This elevation was shown to be mediated by activation of the phosphatidylinositol-phospholipase C/inositol 1,4,5-trisphosphate receptor/Ca 2+ /protein kinase C signaling pathway downstream of glucagon-like peptide-1 receptor activation. Moreover, multielectrode array recordings revealed that glucagon-like peptide-1 functionally augmented the photoresponses of ON-type retinal ganglion cells. Optomotor response tests demonstrated that diabetic rats exhibited reductions in visual acuity and contrast sensitivity that were significantly ameliorated by topical administration of glucagon-like peptide-1. These results suggest that glucagon-like peptide-1 facilitates the release of γ-aminobutyric acid onto retinal ganglion cells through the activation of glucagon-like peptide-1 receptor, leading to the de-excitation of retinal ganglion cell circuits and the inhibition of excitotoxic processes associated with diabetic retinopathy. Collectively, our findings indicate that the γ-aminobutyric acid system has potential as a therapeutic target for mitigating early-stage diabetic retinopathy. Furthermore, the topical administration of glucagon-like peptide-1 eyedrops represents a non-invasive and effective treatment approach for managing early-stage diabetic retinopathy.
Key numbers
183%
Increase in mIPSC Frequency
Average frequency of mIPSCs in RGCs after GLP-1 treatment compared to control.
1696 ± 49.52 cells/mm
RGC Density in Diabetic Rats
RGC density in peripheral areas of diabetic rats treated with GLP-1.
0.2 ± 0.01 cpd
Visual Acuity Improvement
Average visual acuity in diabetic rats treated with GLP-1 compared to untreated.
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