TY - JOUR
T1 - Physiologic brain activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-β
AU - Suberbielle, Elsa
AU - Sanchez, Pascal E.
AU - Kravitz, Alexxai V.
AU - Wang, Xin
AU - Ho, Kaitlyn
AU - Eilertson, Kirsten
AU - Devidze, Nino
AU - Kreitzer, Anatol C.
AU - Mucke, Lennart
N1 - Funding Information:
We thank D.J. Selkoe (Harvard Medical School) and D.M. Walsh (Conway Institute and University College Dublin) for CHO-7PA2 cells; N. Sakane, E. Verdin and L. Verret for comments on the manuscript; H. Kassler for advice on γ-irradiation; D. Davalos for advice on confocal imaging; D. Pathak for advice on live cell imaging; H. Solanoy, M. Thwin, C. Wang and G.-Q. Yu for technical support; A.L. Lucido for editorial review; J. Carroll, T. Roberts, G. Maki and C. Goodfellow for preparation of graphics; and M. Dela Cruz for administrative assistance. The study was supported by US National Institutes of Health grants AG011385, AG022074 and NS065780 to L.M. and a gift from the S.D. Bechtel, Jr. Foundation.
PY - 2013/5
Y1 - 2013/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84876940238&partnerID=8YFLogxK
U2 - 10.1038/nn.3356
DO - 10.1038/nn.3356
M3 - Article
C2 - 23525040
AN - SCOPUS:84876940238
VL - 16
SP - 613
EP - 621
JO - Nature Neuroscience
JF - Nature Neuroscience
SN - 1097-6256
IS - 5
ER -