Activity DEPendent Transposition (ADEPT) and the Aging Brain

Neurons adapt to stimuli through activity dependent changes to their transcriptome, a process mediated by immediate-early gene networks.  Recent findings that transcriptional activation of neuronal immediate-early genes requires the formation of controlled DNA double-strand breaks (DSBs) has come as a surprise and has profound implications for neuronal function, especially in the aging brain.  Here we review recent literature surrounding the phenomena of activity-dependent DNA DSBs in neurons and how this process may be exploited by transposable elements (TEs) in both naïve and aging neurons.  We hypothesize the existence of Activity DEPendent Transposition (ADEPT), where neuronal excitation is able to induce genomic rearrangements through either de novo integration of TEs or by homology-directed recombination of TE-derived repetitive sequences.  Epigenetic drift may cause the magnitude of ADEPT to increase with age, leading to genome instability, which we suggest presages most, if not all, neurodegenerative diseases.