Scientific Report 2003-2004 - Cleveland Clinic Lerner Research ...

Functional Consequences of HereditaryRetinal DiseaseOur laboratory is interested in hereditarydisorders that affect the outer retinallayers. These layers contain the rod andcone photoreceptors and the main second-orderretinal neuron, the bipolar cell. By usingappropriate stimulus conditions, the activity ofeach of these cell types can be monitored usingthe electroretinogram(ERG). In the mammalianretina, this method isparticularly useful fordiscerning the cones andbipolar cells, which arefar less numerous thanare rod photoreceptors,yet are key to manyblinding disorders.An importantfocus of our research ison congenital stationarynight blindness (CSNB),a class of retinal disorderin which communicationbetween photoreceptorsand bipolar cells issomehow disrupted. Wehave identified twomouse models of CSNB.One model, which wenamed nob (no b-wave),involves a naturallyoccurring X-linked trait.We have recently identified the nob gene product(nyctalopin), confirming prior results that the nobmouse might provide a model for CSNB Type 1.A closely related form of CSNB involvesnull mutations in the α 1Fsubunit of the L-typecalcium channel. Mice lacking the β 2subunit ofthis calcium channel in the central nervoussystem closely model the functional abnormalitiesfound in CSNB Type 2. In addition to indicatingthat the α 1Fsubunit depends critically upon theβ 2subunit to form a functional channel, thismutant mouse provides a model in which todefine the pathophysiological mechanismsNeal S. Peachey, Ph.D.underlying this rare retinal disorder. Besidescharacterizing these models, we have establishedan ERG-based screen with which to identifyadditional mutant lines generated by large-scalemutagenesis and to use these animals to identifynovel candidate genes for human CSNB.A second avenue of research involves thepossibility that visualfunction can be restored to aretina blinded by photoreceptordegeneration.Although this situation isencountered in retinitispigmentosa and age-relatedmacular degeneration, thereare few treatment options tooffer affected patients. Incollaboration withOptobionics Corporation, weare carrying out studies toevaluate prototype implantdevices that are designed toelectrically stimulate theouter retina from thesubretinal space. Implantedanimals are evaluated postoperativelyusing a variety oftechniques to establishimplant durability andbiocompatibility. Theseresults are used to identifyimplant designs suitable forapplication to animal models of photoreceptordegeneration, where the potential of this retinalprosthetic may be better evaluated.A general focus of the laboratory continuesto be development and evaluation of assays withwhich to better understand the functional effectsof gene manipulation on the mouse retina. Wehave now established protocols for evaluatingfunction of every cell type in the neural retina,and for the retinal pigment epithelium. As aresult, we can now thoroughly examine theimpact of experimental manipulation in themouse retina.THE PEACHEYLABORATORYPROJECT SCIENTISTMarc Schiavone, Ph.D.RESEARCH ASSOCIATESSherry Ball, Ph.D.Jiang WuTECHNICAL ASSOCIATESMelissa BlumBrett HanzlicekBoth at VA Medical Ctr.,Cleveland, OHCOLLABORATORSKenneth Alexander, Ph.D. 1Alan Chow, M.D. 2Steven Fliesler, Ph.D. 3Ronald Gregg, Ph.D. 4Vance Lemmon, Ph.D. 5Maureen McCall, Ph.D. 4Machelle Pardue, Ph.D. 61UIC Eye Center, Univ. ofIllinois, Chicago, IL2Optobionics Corporation,Wheaton, IL3Eye Inst., St. Louis University,St. Louis, MO4Univ. of Louisville, Louisville,KY5Case Western Reserve Univ.,Cleveland, OH6Veterans Affairs Medical Ctr.and Emory Univ., Atlanta, GABall, S.L., Powers, P.A., Shin, H.-S., Morgans, C.W., Peachey, N.S., and R.G. Gregg (2002) Role of the β 2subunit of voltage dependent calciumchannels in the retinal outer plexiform layer. Invest. Ophthalmol. Vis. Sci. 43:1595-1603.McCall, M.A., Lukasiewicz, P.D., Gregg, R.G., and N.S. Peachey (2002) Elimination of the ρ1 subunit abolishes GABA Creceptor expressionand alters visual processing in the mouse retina. J. Neurosci. 22:4163-4174.Krishna, V.R., Alexander, K.R., and N.S. Peachey (2002) Temporal properties of the mouse cone electroretinogram. J. Neurophysiol. 87:42-48.Peachey, N.S., Stanton, J.B., and A.D. Marmorstein (2002) Noninvasive recording and response characteristics of the rat DC electroretinogram.Vis. Neurosci. 19:693-701.Gregg, R.G., Mukhopadhyay, S., Candille, S.I., Ball, S.L., Pardue, M.T., McCall, M.A., and N.S. Peachey (2003) Identification of the gene andthe mutation responsible for the mouse nob phenotype. Invest. Ophthalmol. Vis. Sci. 44:378-384.165