Abstract
Purpose: :
We report that retinal ganglion cells exhibit abnormal activity patterns in an animal model of tuberous sclerosis, an inherited neurologic disease with abnormal up-regulation of the intracellular mTOR pathway and characterized in part by aberrant optic nerve projections to the lateral geniculate nucleus. We sought to determine the effect of down-regulating this pathway, and found that the aberrant ganglion cell activity may be suppressed by administration of rapamycin, a potent mTOR inhibitor.
Methods: :
In vitro multielectrode recording monitored spontaneous activity in retinas of Tsc2+/- mice, which harbour a homologous mutation known to cause tuberous sclerosis in humans. Identical recordings were made in Tsc2+/+ controls at ages ranging from P7-P90, before and after bath application of 200 nM rapamycin.
Results: :
At P7-8, Tsc2+/- retinas displayed spontaneous "waves" of correlated ganglion cell bursting with slightly lower frequency than in control retinas. By P14, most ganglion cells exhibited elevated spontaneous firing rates with a complex temporal structure. Rapamycin gradually attenuated this hyperactivity over 1-2 hours, and the abnormal temporal firing patterns progressively resolved.
Conclusions: :
This is the first demonstration of abnormal retinal physiology in tuberous sclerosis, a complex multisystem disease characterized by abnormal cellular growth and axonal misdirection. Previous studies have demonstrated that 1) distorted temporal structure can be associated with abnormal ganglion cell axon projections to central visual system structures, and 2) axonal projections to these structures are misdirected in Tsc2+/- mice. Our findings demonstrate that these aberrant projections also are associated with abnormal spontaneous activity in Tsc2+/- retinas. They suggest that abnormal activity patterns may occur in other diseases without previously suspected retinal dysfunction, and may disrupt the organization of retinal projections to central visual structures. Moreover, they indicate that such activity may be modulated by clinically available agents regulating intracellular pathways, suggesting possible treatment avenues.
Keywords: retinal degenerations: cell biology • ganglion cells • plasticity