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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid beta-Peptides / metabolism*
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Amyloid beta-Protein Precursor / genetics
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Animals
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Animals, Newborn
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Cells, Cultured
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Cerebral Cortex / cytology
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Cerebral Cortex / drug effects
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Channelrhodopsins
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Corpus Striatum / drug effects
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Corpus Striatum / metabolism
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Corticosterone / blood
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DNA Breaks, Double-Stranded*
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Disease Models, Animal
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Excitatory Amino Acid Antagonists / pharmacology
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Exploratory Behavior / drug effects
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Exploratory Behavior / physiology
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Gene Expression Regulation / drug effects
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Hippocampus / cytology
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Hippocampus / drug effects
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Histones / metabolism
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Humans
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Neurons / drug effects
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Neurons / physiology*
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Photic Stimulation
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Quinoxalines / pharmacology
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Reactive Oxygen Species / metabolism
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Stress, Physiological / physiology
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Valine / analogs & derivatives
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Valine / pharmacology
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tau Proteins / genetics
Substances
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Channelrhodopsins
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Excitatory Amino Acid Antagonists
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H2AX protein, mouse
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Histones
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Mapt protein, mouse
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Quinoxalines
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Reactive Oxygen Species
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tau Proteins
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2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline
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2-amino-5-phosphopentanoic acid
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Valine
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Corticosterone