Age-Related Formation of Ectopic Synapses in the Mouse Retina Is Suppressed by Calorie Restriction Through Mitochondrial Functions

Abstract

Purpose: : Ectopic synaptic interaction between rod photoreceptor cells and secondary neurons is characterized by the retraction of photoreceptor cell axons and subsequent extension of dendrites of bipolar and horizontal cells. This abnormal synaptic structure is observed during the aging process in human and mice. The purpose of this study was to test the effect of calorie restriction and mitochondorial DNA (mtDNA) mutations on the appearance of ectopic synapses.

Methods: : In this study, a mouse model with accelerated age-related impairment of mitochondorial functions were used. Polg^D257A/D257A mice carry a two-base substitution in DNA polymerase γ (Polg), which impairs its mtDNA proof-reading ability. Because of this defect, Polg^D257A/D257A mice accumulate mtDNA mutations at a much higher rate compared to wild-type mice. Wild-type and Polg^D257A/D257A mice were divided into two groups: the control group with normal diet and the calorie-restricted group. To assess the synaptic morphology, we performed marker studies to visualize different cell types, pre- and post-synaptic structures in the retina in each group of mice at 13-15 months of age.

Results: : In wild-type mice that were aged on normal diet, we observed that second-order neurons ectopically extend neurites into the outer nuclear layer (ONL) and photoreceptor presynapses are ectopically localized in the ONL. Ectopic synapses were more abundantly observed in the peripheral retina. Age-matched calorie-restricted wild-type mice show a smaller number of ectopic synapses. The suppressive effect of calorie restriction on ectopic synapses was not observed in mice homozygous for the Polg^D257A allele. The abundance of ectopic synapses in Polg^D257A/D257A mice either with or without calorie restriction was similar to that in wild-type mice on normal diet.

Conclusions: : Calorie restriction protects mice from age-associated abnormal synaptic morphologies in the retina. Since accelerated accumulation of mtDNA mutations inhibits this effect, protection by calorie restriction may be mediated through mitochondrial functions in the photoreceptor cells.

Keywords: aging • synapse • mitochondria