SUMMARY Neuronal activity causes the rapid expression of immediate early genes that are crucial for experience-driven changes to synapses, learning, and memory. Here, using both molecular and genome-wide next-generation sequencing methods, we report that neuronal activity stimulation triggers the formation of DNA double strand breaks (DSBs) in the promoters of a subset of early-response genes, including Fos, Npas4, and Egr1. Generation of targeted DNA DSBs within Fos and Npas4 promoters is sufficient to induce their expression even in the absence of an external stimulus. Activity-dependent DSB formation is likely mediated by the type II topoisomerase, Topoisomerase IIβ (Topo IIβ), and knockdown of Topo IIβ attenuates both DSB formation and early-response gene expression following neuronal stimulation. Our results suggest that DSB formation is a physiological event that rapidly resolves topological constraints to early-response gene expression in neurons.

The integrity of our genetic material is under constant attack from numerous endogenous and exogenous agents. The consequences of a defective DNA damage response are well studied in proliferating cells, especially with regards to the development of cancer, yet its precise roles in the nervous system are relatively poorly understood. Here we attempt to provide a comprehensive overview of the consequences of genomic instability in the nervous system. We highlight the neuropathology of congenital syndromes that result from mutations in DNA repair factors and underscore the importance of the DNA damage response in neural development. In addition, we describe the findings of recent studies, which reveal that a robust DNA damage response is also intimately connected to aging and the manifestation of age-related neurodegenerative disorders such as Alzheimer’s disease and amyotrophic lateral sclerosis.

Summary Defects in DNA repair have been linked to cognitive decline with age and neurodegenerative disease. Yet the mechanisms that protect neurons from genotoxic stress remain largely obscure. In this report, we characterize the roles of the NAD+-dependent deacetylase, SIRT1, in the neuronal response to DNA double-strand breaks (DSBs). We show that SIRT1 is rapidly recruited to DSBs in postmitotic neurons, where it exhibits a synergistic relationship with ATM. SIRT1 recruitment to breaks is ATM-dependent; however, SIRT1 also stimulates ATM auto-phosphorylation and activity and stabilizes ATM at DSB sites. Upon DSB induction, SIRT1 also binds the neuroprotective class I histone deacetylase, HDAC1. We show that SIRT1 deacetylates HDAC1 and stimulates its enzymatic activity, which is necessary for DSB repair through the nonhomologous end-joining (NHEJ) pathway. HDAC1 mutants that mimic a constitutively acetylated state render neurons more susceptible to DNA damage, whereas pharmacological SIRT1 activators that promote HDAC1 deacetylation also reduce DNA damage in two mouse models of neurodegeneration. We propose that SIRT1 is an apical transducer of the DSB response and that SIRT1 activation offers an important therapeutic avenue in neurodegeneration.

How neurons develop their morphology is an important question in neurobiology. Here we describe a novel pathway that specifically affects the formation of basal dendrites and axonal projections in cortical pyramidal neurons. We report that thousand-and-one-amino acid 2 (TAO2) kinase plays an essential role in dendrite morphogenesis. TAO2 down-regulation impairs basal dendrite formation in vivo without affecting apical dendrites. Moreover, TAO2 interacts with Neuropilin 1 (Npn1), a receptor protein that binds the secreted guidance cue Semaphorin 3A (Sema3A). TAO2 over-expression restores dendrite formation in cultured cortical neurons from Npn1Sema− mice, which express Npn1 receptors incapable of binding Sema3A. TAO2 over-expression also ameliorates the basal dendrite impairment resulting from Npn1 down-regulation in vivo. Finally, Sema3A and TAO2 modulate the formation of basal dendrites through the activation of the c-Jun N-Terminal Kinase (JNK). These results delineate a pathway whereby Sema3A and Npn1 transduce signals through TAO2 and JNK to regulate basal dendrite development in cortical neurons.