Rearing Light Intensity Affects Inner Retinal Pathology in a Mouse Model of X-Linked Retinoschisis but Does Not Alter Gene Therapy OutcomeEffects of Rearing Light Intensity on Rs1-KO Mouse

摘要

Purpose:Totesttheeffectsofrearinglightintensityonretinalfunctionandmorphologyintheretinoschisisknockout(Rs1-KO)mousemodelofX-linkedretinoschisis,andwhetheritaffectsfunctionaloutcomeofRS1genereplacement.Methods:Seventy-sixRs1-KOmicewererearedineithercycliclowlight(LL,20lux)ormoderatelight(ML,300lux)andanalyzedat1and4months.Retinalfunctionwasassessedbyelectroretinogramandcavitysizebyopticalcoherencetomography.Expressionofinward-rectifierK+channel(Kir4.1),waterchannelaquaporin-4(AQP4),andglialfibrillaryacidicprotein(GFAP)wereanalyzedbyWesternblotting.Inaseparatestudy,Rs1-KOmicerearedinLL(n=29)orML(n=27)receivedaunilateralintravitrealinjectionofscAAV8-hRs-IRBPat21days,andfunctionaloutcomewasevaluatedat4monthsbyelectroretinogram.Results:At1month,nofunctionalorstructuraldifferenceswerefoundbetweenLL-orML-rearedRs1-KOmice.At4months,ML-rearedRs1-KOmiceshowedsignificantreductionofb-waveamplitudeandb-/a-waveratiowithnochangesina-wave,andasignificantincreaseincavitysize,comparedtoLL-rearedanimals.ModeratelightrearingincreasedKir4.1expressioninRs1-KOmiceby4months,butnotAQP4andGFAPlevels.AdministrationofscAAV8-hRS1-IRBPtoRs1-KOmiceshowedsimilarimprovementofinnerretinalERGfunctionindependentofLLorMLrearing.Conclusions:Rearinglightconditionsaffectthedevelopmentofretinalcavitiesandpost-photoreceptorfunctioninRs1-KOmice.However,theeffectofrearinglightintensitydoesnotinteractwiththeefficacyofRS1genereplacementinRs1-KOmice.