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

Elsa Suberbielle, Pascal E. Sanchez, Alexxai V. Kravitz, Xin Wang, Kaitlyn Ho, Kirsten Eilertson, Nino Devidze, Anatol C. Kreitzer, Lennart Mucke

Research output: Contribution to journalArticle

213 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)613-621
Number of pages9
JournalNature neuroscience
Volume16
Issue number5
DOIs
StatePublished - May 1 2013
Externally publishedYes

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    Suberbielle, E., Sanchez, P. E., Kravitz, A. V., Wang, X., Ho, K., Eilertson, K., Devidze, N., Kreitzer, A. C., & Mucke, L. (2013). Physiologic brain activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-β. Nature neuroscience, 16(5), 613-621. https://doi.org/10.1038/nn.3356