Format

Send to

Choose Destination
Nat Neurosci. 2013 May;16(5):613-21. doi: 10.1038/nn.3356. Epub 2013 Mar 24.

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

Author information

1
Gladstone Institute of Neurological Disease, San Francisco, California, USA.

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.

Comment in

PMID:
23525040
PMCID:
PMC3637871
DOI:
10.1038/nn.3356
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center