Early loss of synaptic protein PSD-95 from rod terminals of rhodopsin P347L transgenic porcine retina

Retinitis pigmentosa (RP), a type of retinal degeneration involving first r od and then slow cone photoreceptor degeneration, can be caused by any of a number of mutations in different genes. In the cases of mutations affectin g rod-specific genes such as rhodopsin, it is unclear how the mutations may cause degeneration of cones. We have used the porcine retina, which is rod -dominated and has an abundance of cones, to study the mutation-induced cha nges in both rod and cone photoreceptors. Like patients with the same mutat ion, rhodopsin P347L transgenic swine manifest rod-cone degeneration. In ad dition, the rod bipolar cells fail to form synaptic connections with rods; instead, they form ectopic synapses with cones. The mechanisms that prevent the formation of the rod-rod bipolar cell synaptic connection are not know n. We used specific antibodies and immunocytochemistry to show that the syn aptic protein, PSD-95, is present in both normal and transgenic porcine ret inas. During neonatal development, however, PSD-95 is lost from rod termina ls in the transgenic swine. This loss is virtually complete (90%) by postna tal day 5, at a time when greater than 80% of rod cell bodies still remain. Furthermore, the remaining rods retain their outer segments and their gros s morphology appears relatively normal. In contrast, PSD-95 expression cont inues in cone terminals, even in 10-month-old transgenic swine, where the r ods have all disappeared and the cones show signs of severe degeneration. T hese results suggest that loss of PSD-95 may not be a general consequence o f the deteriorating cell. Rather, the very early and selective loss of PSD- 95 from the rod terminals may be causally related to the absence of rod-rod bipolar cell synapses in the rhodopsin P347L transgenic retina. (C) 2000 E lsevier Science B.V. All rights reserved.