[Animal models of human retinal and optic nerve diseases analysed using electroretinography]

Investigations of animal models with diseases found in humans are important to the understanding of their pathophysiology and for developing new treatments. Both naturally occurring and genetically-manipulated animal models of human retinal and optic nerve diseases have been studied in this manner. Electroretinography (ERG) is valuable for the evaluation of the visual function of animal models, because a layer-by-layer assessment of the retina can be done objectively. We used ERGs to analyze the visual functions of animal models of human retinal and and optic nerve diseases. To investigate the contribution of the cone ON- and OFF-pathways to the mouse photopic ERGs, we studied the properties of the photopic ERGs of metabotropic glutamate receptor subtype 6-deficient mice. The results of the ERG and the effect of an intravitreous injection of cis-2,3 piperidine dicarboxylic acid (PDA) in these mice suggest that the contribution of the post-synaptic ON-pathway to the photopic ERG of mice is larger than that of the OFF-pathway. The ERGs of pikachurin-deficient mice had normal a-waves with severely delayed b-waves, indicating that the signal transmission from the photoreceptors to the bipolar cells was impaired in these mutant mice. We also generated a rabbit model of retinitis pigmentosa (RP), the rhodopsin P347L transgenic (Tg) rabbit, by using bacterial artificial chromosome (BAC) transgenesis. These rabbits showed a rod-dominant, progressive retinal degeneration with marked regional variations in the loss of photoreceptors. All ERG components of the Tg rabbits decreased progressively with the a-waves more affected than the b-waves, and with the oscillatory potentials (OPs) the best preserved. Interestingly, the OP amplitudes of young Tg rabbits were significantly larger than those of wild-type rabbits. Pharmacological experiments showed that the significantly larger OPs in young Tg rabbits resulted from secondary alterations in the inner retinal function. This type of supernormal OPs has also been observed in the focal macular ERGs of some RP patients. We succeeded also in eliciting focal photopic negative responses (PhNRs) from the macula of rhesus monkeys with a red stimulus spot on a blue background illumination. The amplitudes of the focal macular PhNRs were relatively large when compared to those of the a- and b-waves. We found that the PhNR of the upper macular area was significantly larger than that of the lower macula, and the PhNR of the nasal macula was significantly larger than that of the temporal macula. Results of intravitreal injection of tetrodotoxin(TTX) in monkeys suggest that these asymmetries of PhNR are mainly caused by TTX-sensitive spiking neurons of the inner retina. Thus, ERGs have proven to be quite useful for objectively studying the visual functions in various animal models of human retinal and optic nerve diseases.