title: Physiologic brain activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-β.
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.
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California, USA.
authors.forename: Elsa
authors.initials: E
authors.lastname: Suberbielle
authors.forename: Pascal E
authors.initials: PE
authors.lastname: Sanchez
authors.forename: Alexxai V
authors.initials: AV
authors.lastname: Kravitz
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Kaitlyn
authors.initials: K
authors.lastname: Ho
authors.forename: Kirsten
authors.initials: K
authors.lastname: Eilertson
authors.forename: Nino
authors.initials: N
authors.lastname: Devidze
authors.forename: Anatol C
authors.initials: AC
authors.lastname: Kreitzer
authors.forename: Lennart
authors.initials: L
authors.lastname: Mucke
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D000075402:Channelrhodopsins; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D053903:DNA Breaks, Double-Stranded; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010775:Photic Stimulation; D011810:Quinoxalines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological / Q000502:physiology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D016875:tau Proteins / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000075402:Channelrhodopsins; D003345:Corticosterone; D018691:Excitatory Amino Acid Antagonists; D006657:Histones; D011810:Quinoxalines; D017382:Reactive Oxygen Species; D014633:Valine; D016875:tau Proteins; C558298:Mapt protein, mouse; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C056639:2-amino-5-phosphopentanoic acid; C475961:gamma-H2AX protein, mouse