Synaptic Proteome Changes in a DNA Repair Deficient <i>Ercc1</i> Mouse Model of Accelerated Aging

Abstract

Cognitive decline is one of the earliest hallmarks of both normal and pathological brain aging. Here we used <i>Ercc1</i> mutant mice, which are impaired in multiple DNA repair systems and consequently show accelerated aging and progressive memory deficits, to identify changes in the levels of hippocampal synaptic proteins that potentially underlie these age-dependent deficits. Aged <i>Ercc1</i> mutant mice show normal gross hippocampal dendritic morphology and synapse numbers, and <i>Ercc1</i> mutant hippocampal neurons displayed normal outgrowth and synapse formation <i>in vitro</i>. However, using isobaric tag for relative and absolute quantification (iTRAQ) of hippocampal synaptic proteins at two different ages, postnatal days 28 and 112, we observed a progressive decrease in synaptic ionotropic glutamate receptor levels and increased levels of G-proteins and of cell adhesion proteins. These together may cause long-term changes in synapse function. In addition, we observed a downregulation of mitochondrial proteins and concomitant upregulation of Na,K-ATPase subunits, which might compensate for reduced mitochondrial activity. Thus, our findings show that under conditions of apparent intact neuronal connectivity, levels of specific synaptic proteins are already affected during the early stages of DNA damage-induced aging, which might contribute to age-dependent cognitive decline