Loss of photic entrainment and altered free-running circadian rhythms in math5^-/- mice

Mammalian free-running circadian rhythms are entrained to the external light/dark cycle by photic signaling to the suprachiasmatic nuclei via the retinohypothalamic tract (RHT). We investigated the circadian entrainment and clock properties of math5^-/- mutant mice. math5 is a critical regulator of retinal ganglion cell development; math5^-/- mice show severe optic nerve hypoplasia. By anterograde cholera toxin B tracing, we find that math5^-/- mice do not develop an identifiable RHT pathway. This appears to be attributable to agenesis or dysgenesis of the majority of RHT-projecting retinal ganglion cells. math5^-/- mice display free-running circadian rhythms with a period ∼1 hr longer than B6/129 controls (24.43 ± 0.10 vs 23.62 ± 0.19 hr; p < 0.00001). The free-running period of heterozygote mice is indistinguishable from that of controls. math5^-/- mice show no entrainment to light/dark cycles, whereas heterozygote mice show normal entrainment to both 12 hr light/dark cycles and to a 1 hr skeletal photoperiod. math5^-/- mice show reduced ability to entrain their rhythms to the nonphotic time cue of restricted running wheel access but demonstrate both free-running behavior and entrained anticipation of wheel unlocking in these conditions, suggesting the presence of a second diurnal oscillatory system in math5^-/- animals. These results demonstrate that retinal ganglion cell input is not necessary for the development of a free-running circadian timekeeping system in the suprachiasmatic nucleus but is important for both photic entrainment and determination of the free-running period.