Editors' ChoiceNeuroscience

Damaging Thoughts

Sci. Signal.  14 May 2013:
Vol. 6, Issue 275, pp. ec107
DOI: 10.1126/scisignal.2004322

DNA damage in neurons may enable chromatin remodeling and gene expression under physiological conditions and may lead to cell death under pathophysiological conditions. A marker of double-stranded DNA breaks is γH2A.X (the phosphorylation of the histone H2A at Ser139). Suberbielle et al. (see also Herrup et al.) found that hAPP-J20 mice, which are a model for Alzheimer’s disease, had a higher number of γH2A.X-positive neurons than wild-type mice and that adding β-amyloid (Aβ) oligomers to cultured wild-type neurons increased the number of γH2A.X foci. Wild-type mice that explored a novel environment showed a higher number of γH2A.X-positive neurons than those that did not, a response that returned to baseline after a 24-hour recovery period. In addition, the number of γH2A.X foci was increased by visual stimulation and passive activation of the striatum by optogenetic stimulation. The number of γH2A.X foci was normalized in hAPP-J20 mice by genetic deficiency in the microtubule-binding protein tau or treatment with the anti-epilepsy drug levetiracetam, both of which reduce the aberrant neuronal activity, manifested as epileptiform spikes and nonconvulsive seizures, in hAPP-J20 mice. In cultured wild-type neurons, the increase in γH2A.X foci caused by the addition of Aβ oligomers was reduced by a sodium channel blocker or antagonists of AMPA- or N-methyl-D-aspartate (NMDA)–type glutamate receptors and was enhanced under culture conditions that favored the stimulation of extrasynaptic NMDA receptors rather than that of intrasynaptic receptors. Thus, increased neuronal activity, whether triggered by normal stimulation or behaviors or by pathological amounts of Aβ, leads to double-stranded DNA breaks through an extrasynaptic NMDA receptor-dependent mechanism.

E. Suberbielle, P. E. Sanchez, A. V. Kravitz, X. Wang, K. Ho, K. Eilertson, N. Devidze, A. C. Kreitzer, L. Mucke, Physiologic brain activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-β. Nat. Neurosci.16, 613–621 (2013). [PubMed]

K. Herrup, J. Chen, J. Li, Breaking news: Thinking may be bad for DNA. Nat. Neurosci. 16, 518–519 (2013). [PubMed]

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