Abstract
Purpose :
Inner retinal dysfunction and thinning are features of early diabetic retinal disease (DRD), preceding the clinical diagnosis of diabetic retinopathy (DR). The underlying molecular mechanisms remain unclear. Recently, decreased levels of the synaptic proteins neurexins (Nrxns) have been described in the brain of a mouse model of diabetes but little is known about the role of Nrxns in the retina. The purpose of this study is to define a potential role of neurexin 1 (Nrxn1) in early diabetic retinal dysfunction. We hypothesize that Nrxn1 dysregulation occurs in the inner retina during the early phases of DRD.
Methods :
Intraperitoneal injection of 60mg/kg streptozotocin (STZ) or vehicle was administered daily for five days to 8-10 week old male C57BL/6J mice, and those with blood glucose > 250 mg/dL were considered to have diabetes. Optical coherence tomography (OCT), electroretinography (ERG), and fluoresecein angiography were performed at 6 weeks after induction of diabetes. At this timepoint, retinal tissues were collected and analyzed for Nrxn1 protein expression by Western blot. Cell-type-localization and transcript expression was assessed using RNAscope in situ hybridization.
Results :
Six weeks after STZ treatment, diabetic mice exhibited functional deficits on ERG and inner retinal thinning on OCT. Importantly, these alterations were noted in the absence of vascular leakage, recapitulating the neurodegenerative features of early DRD. Nrxn1 protein expression was significantly decreased in the diabetic retina. RNAscope in situ analyses revealed that neurexin transcripts are predominantly expressed in the inner retina, including in the retinal ganglion cells (RGCs). Furthermore, RGCs in the peripheral retina of diabetic mice expressed decreased Nrxn1 transcript compared with controls.
Conclusions :
Our results confirm that at 6 weeks after diabetes induction, STZ-treated mice exhibit the neurodegenerative features of early DRD in the absence of vascular leakage. Decreased Nrxn1 expression in the inner retina, namely RGCs, may contribute to the phenotype of early DRD.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.