The G protein β subunit 3 (Gβ3) is part of the G-protein signaling cascade in retinal ON bipolar cells (BCs), and cone photoreceptors. Knockout of the encoding gene (Gnb3) in mice results in reduced cone photoreceptor sensitivity and marked impairment of both rod and cone ON BC signaling. The latter is revealed as a severe reduction in both the dark- and light-adapted b-wave of the electroretinogram (ERG). Mutations in GNB3 have been recently reported as an apparently stationary condition associated with a variable degree of loss of rod ERG b-wave and the ON BC component of the light-adapted ERG. Gnb3-/- rats were developed and similar to Gnb3 -/- mice had a severe reduction in rod ON bipolar cell signaling. However, in contrast to the mouse model, cone ON BC signaling was relatively well preserved. Application of L-AP4, a blocker of photoreceptor to ON BC signaling, removed the remaining b-wave from the cone ERG confirming it originated from cone ON BCs. Single cell recording from Gnb3-/- retinal slices showed some cone ON BC were functional while rod ON BCs were not functional. Retinal gene therapy are being extensively used as novel treatments to genetic diseases in the retina. Here we used adeno- associated viral (AAV) vectors developed to target retinal bipolar cells. Intravitreal delivery at early ages (P2) showed to be a promising method targeting bipolar cells in rats. Gnb3-/- rats were treated with an AAV containing a copy of the mouse GNB3. cDNA in one eye and a human GFP construct as a procedural control in the other eye. No functional rescue was observed on the time course of the study (3 months) but presence of mRNA was noticed in all the eyes analyzed by qRT-PCR. The Gnb3-/- rat is a useful additional model for the study of retinal ON bipolar cell signaling, and as a model for human Gβ3-associated retinopathy.
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