Abstract
Purpose :
Glaucoma is a group of progressive disorders of optic nerve due to the retina ganglion cells(RGC) dysfunction and death. The pathophysiology of glaucoma is multifactorial and not completely understood. The nee mouse model with homozygous for spontaneously arising Sh3pxd2bnee mutation (background C57BL/6J) exhibits features of severe congenital glaucoma, including high intraocular pressure (IOP), RGC loss, and degenerated optic nerve. Other than glaucoma, nee mice show craniofacial cardia and skeletal abnormalities. We previously reported CaMKIIaT286D, a constitutively active mutant of CaMKIIa at autophosphorylated state, protects RGCs from multiple experimental injuries and slows down disease progression in induced and genetic animal models of glaucoma. Here we investigated if CaMKIIαT286D could preserve RGC and their function in nee mice.
Methods :
B6.Sh3pxd2b nee mice were maintained in heterozygote x heterozygote breeding. Homozygous litters(nee) were selected for experiment and wild-type (WT) were used as control group. We performed intravitreal injection for AAV2-mediated gene transfer of CaMKIIαT286D in one eye randomly, and the other eye was used as negative control. Immunostaining was used to study RGC loss with RGC marker Tubulin β3 (Tuj1). Pattern electroretinography (PERG) response was recorded to test whether CaMKIIαT286D could maintain RGC function.
Results :
We quantified RGCs in nee and WT from 2 to 16 weeks of age. There was no RGC loss in nee and WT at 2 weeks and WT. Starting from 4 weeks, IOP increased to 23.5 ± 5 mm Hg and RGC loss was seen in nee, with further 90% loss by 16weeks, indicating severe RGC damage. With overexpression of CaMKIIαT286D, RGC number was rescued to 90% of WT at 4 weeks, 80% of WT at 12 weeks. PERG response in the eye with injection of CamkIIT286D was preserved to the level comparable to these in WT group, which was completely lost in the other eye without CaMKIIαT286D injection
Conclusions :
Our study indicates that CaMKIIαT286D played a key role in maintaining RGC survival in nee mice, a nodel of human congenital glaucoma. Neuroprotective studies using nee mice offers significant advantages for finding potential therapeutic strategies to treat glaucoma.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.