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1From the Departments of Human Genetics and 2Internal Medicine, University of Michigan, Ann Arbor, Michigan; the Divisions of 4Developmental Biology and 5Ophthalmology, Children’s Hospital Research Foundation, Department of Pediatrics, University of Cincinnati Medical School, Cincinnati, Ohio; 6Section for Translational Research on Retinal and Macular Degeneration, National Institute on Deafness and Other Communication Disorders, Bethesda, Maryland; 7National Eye Institute, Bethesda, Maryland; 8Center for Functional Genomics, Northwestern University, Evanston, Illinois; and the 9Department of Neurobiology and Physiology, Howard Hughes Medical Institute, Northwestern University, Evanston, Illinois.
PURPOSE. To determine how the absence of retinal ganglion cells (RGCs) in Math5 (Atoh7) mutant mice affects circadian behavior and retinal function.
METHODS. The wheel-running behavior of wild-type and Math5 mutant mice was measured under various light–dark cycle conditions. To evaluate retinal input to the suprachiasmatic nuclei (SCN) anatomically, the retinohypothalamic tracts were labeled in vivo. To assess changes in retinal function, corneal flash electroretinograms (ERGs) from mutant and wild-type mice were compared under dark- and light-adapted conditions. Alterations in retinal neuron populations were evaluated quantitatively and with cell-type–specific markers.
RESULTS. The Math5-null mice did not entrain to light and exhibited free-running circadian behavior with a mean period (23.6 ± 0.15 hours) that was indistinguishable from that of wild-type mice (23.4 ± 0.19 hours). The SCN showed no anterograde labeling with a horseradish peroxidase–conjugated cholera toxin B (CT-HRP) tracer. ERGs recorded from mutant mice had diminished scotopic a- and b-wave and photopic b-wave amplitudes. The scotopic b-wave was more severely affected than the a-wave. The oscillatory potentials (OPs) and scotopic threshold response (STR) were also reduced. Consistent with these ERG findings, a pan-specific reduction in the number of bipolar cells and a smaller relative decrease in the number of rods in mutant mice were observed.
CONCLUSIONS. Math5-null mice are clock-blind and have no RGC projections to the SCN. RGCs are thus essential for photoentrainment in mice, but are not necessary for the development or intrinsic function of the SCN clock. RGCs are not required to generate any of the major ERG waveforms in mice, including the STR, which is produced by ganglion cells in some other species. The diminished amplitude of b-wave, OPs, and STR components in Math5 mutants is most likely caused by the decreased abundance of retinal interneurons.
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