Physiologic brain activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-β

In this study, the authors show that neuronal activity, induced by natural exploration, exposure to visual stimuli or optogenetic probe–mediated stimulation, can induce double-stranded DNA breaks (DSBs) in neurons. The numbers of these DSBs were aggravated in the presence of amyloid precursor protein and depended on extrasynaptic NMDAR activity. We show that a natural behavior, exploration of a novel environment, causes DNA double-strand breaks (DSBs) in neurons of young adult wild-type mice. DSBs occurred in multiple brain regions, were most abundant in the dentate gyrus, which is involved in learning and memory, and were repaired within 24 h. Increasing neuronal activity by sensory or optogenetic stimulation increased neuronal DSBs in relevant but not irrelevant networks. Mice transgenic for human amyloid precursor protein (hAPP), which simulate key aspects of Alzheimer's disease, had increased neuronal DSBs at baseline and more severe and prolonged DSBs after exploration. Interventions that suppress aberrant neuronal activity and improve learning and memory in hAPP mice normalized their levels of DSBs. Blocking extrasynaptic NMDA-type glutamate receptors prevented amyloid-β (Aβ)-induced DSBs in neuronal cultures. Thus, transient increases in neuronal DSBs occur as a result of physiological brain activity, and Aβ exacerbates DNA damage, most likely by eliciting synaptic dysfunction.