A K42E knockin mouse model of RP59 exhibits a negative ERG and defective postsynaptic signal transmission

Abstract

Purpose : We previously generated a murine Dhdds K42E knockin (KI) mouse model of RP59 that exhibited incipient neuroinflammation and gliosis, but no overt retinal degeneration or cell loss, even by 1 year of age. Here, we further evaluated the phenotype of this animal model.

Methods : K42E homozygous (Dhdds^K42E/K42E) KI mice were bred to 4^th generation, and compared to age/sex-matched wildtype (WT) mice. Phenotypes were assessed by electroretinography (ERG, n=8-10), whole cell patch-clamp recordings, and fundus imaging (n=3-4) at postnatal 180 days. Immunohistochemistry (IHC) was performed on retinal frozen sections using antibodies to PKCα, synaptotagmin-1, and ribeye.

Results : Scotopic and photopic ERG a-wave responses were comparable in WT and KI mice. These results were confirmed by single cell recordings. By contrast, KI mice exhibited significant reductions in scotopic b-wave (358±34 µV KI vs. 642±67 µV WT; p <0.01) and photopic b-wave (178±26 µV KI vs. 273±32 µV WT; p <0.05) amplitudes. KI retinas exhibited no overt signs of degeneration or disorganization. IHC did not reveal obvious abnormalities in localization or levels of the markers analyzed, and synaptic ribbons were properly localized and exhibited normal appearance.

Conclusions : This genetic mouse model of RP59 exhibits a negative ERG (reduction in b-wave without a concomitant reduction in a-wave), indicating defective photoreceptor-to-bipolar cell synaptic transmission. The findings suggest that the defect is postsynaptic, involving ON bipolar cells.

This is a 2021 ARVO Annual Meeting abstract.