An Adaptive Role for DNA Double-Strand Breaks in Hippocampus-Dependent Learning and Memory

Abstract

DNA double-strand breaks (DSBs), classified as the most harmful type of DNA damage based on the complexity of repair, lead to apoptosis or tumorigenesis. In aging, DNA damage increases and DNA repair decreases. This is exacerbated in disease, as post-mortem tissue from patients diagnosed with mild cognitive impairment (MCI) or Alzheimer's disease (AD) show increased DSBs. A novel role for DSBs in immediate early gene (IEG) expression, learning, and memory has been suggested. Inducing neuronal activity leads to increases in DSBs and upregulation of IEGs, while increasing DSBs and inhibiting DSB repair impairs long-term memory and alters IEG expression. Consistent with this pattern, mice carrying dominant AD mutations have increased baseline DSBs, and impaired DSB repair is observed. These data suggest an adaptive role for DSBs in the central nervous system and dysregulation of DSBs and/or repair might drive age-related cognitive decline (ACD), MCI, and AD. In this review, we discuss the adaptive role of DSBs in hippocampus-dependent learning, memory, and IEG expression. We summarize IEGs, the history of DSBs, and DSBs in synaptic plasticity, aging, and AD. DSBs likely have adaptive functions in the brain, and even subtle alterations in their formation and repair could alter IEGs, learning, and memory.

Keywords: DNA damage; aging; amifostine; cognition; double-strand brakes; etoposide; hippocampus.

Figure 1

Suggested mechanims of adaptive DSBs. (A) At baseline, transcription is held in pause. Trim28 holds RNA polymerase II (Pol II) in pause, and topological factors prevent the enhancer and promoter regions from interacting. (B) Neuronal activation occurs with the binding of glutamate to NMDARs and AMPARs, allowing an influx of calcium that initiates a signal cascade into the nucleus. Following this cascade, topoisomerase II β initiates a DSB downstream of the transcription start site. The DSB activates ATM, which induces phosphorylation of DNA-PKcs, Trim28, and H2Ax. Trim28 phosphorylation releases Pol II, which then becomes active to induce transcription of IEGs. Additionally, the DSB releases topological constraints, allowing the enhancer and promoter regions to interact.