Selective Disruption of Non-Visual Responses to Light in a Mouse Model of Malattia Leventinese

Abstract

Purpose: : The R345W mutation in EFEMP1 causes Malattia Leventinese, an autosomal dominant eye disease with features similar to age-related macular degeneration. In mice, Efemp1^R345W has subtle pathology, with sub-retinal deposits similar to drusen but an otherwise healthy retinal appearance and a normal electroretinogram. The aim of this study was to determine whether Efemp1^R345W affects non-visual responses to light in mice.

Methods: : Irradiance response relationships were measured for the pupil light reflex and the suppression of running wheel activity - a response to bright light called negative masking. Overall retinal function was measured by the electroretinogram.

Results: : All measured features of the pupil light reflex and the electroretinogram were indistinguishable from wildtype. However, negative masking showed significant hypersensitivity (P<0.0001), with a half maximal response at 0.008microWcm² compared to 1.02microWcm² in wildtype mice.

Conclusions: : These results show that in addition to promoting deposit formation in Bruch’s membrane, the R345W mutation in Efemp1 affects some aspects of retinal function directly. In other mouse models, negative masking hypersensitivity has only been observed with almost complete loss of rod function. In context of a grossly normal ERG and pupil light reflex, this discrete functional phenotype suggests Efemp1^R345W is affecting a specific type of melanopsin expressing cell, and/or the associated conventional photoreceptor input.

Keywords: age-related macular degeneration • photoreceptors: visual performance • pupillary reflex