Deletion of the p85α Regulatory Subunit of Phosphoinositide 3-Kinase in Cone Photoreceptor Cells Results in Cone Photoreceptor Degeneration

PURPOSE. Downregulation of the retinal insulin/mTOR pathway in mouse models of retinitis pigmentosa is linked to cone cell death, which can be delayed by systemic administration of insulin. A classic survival kinase linking extracellular trophic/growth factors with intracellular antiapoptotic pathways is phosphoinositide 3-kinase (PI3K), which the authors have shown to protect rod photoreceptors from stress-induced cell death. The role of PI3K in cones was studied by conditional deletion of its p85 alpha regulatory subunit. METHODS. Mice expressing Cre recombinase in cones were bred to mice with a floxed pi3k gene encoding the p85 alpha regulatory subunit of the PI3K and were back-crossed to ultimately generate offspring with cone-specific p85 alpha knockout (cKO). Cre expression and cone-specific localization were confirmed by Western blot analysis and immunohistochemistry (IHC), respectively. Cone structural integrity was determined by IHC using peanut agglutinin and an M-opsin-specific antibody. Electroretinography (ERG) was used to assess rod and cone photoreceptor function. Retinal structure was examined by light and electron microscopy. RESULTS. An age-related cone degeneration was found in cKO mice, evidenced by a reduction in photopic ERG amplitudes and loss of cone cells. By 12 months of age, approximately 78% of cones had died, and progressive disorganization of synaptic ultrastructure was noted in surviving cone terminals in cKO retinas. Rod viability was unaffected in p85 alpha cKO mice. CONCLUSIONS. The present study suggests that PI3K signaling pathway is essential for cone survival in the mouse retina. (Invest Ophthalmol Vis Sci. 2011;52:3775-3783) DOI: 10.1167/iovs.10-7139