GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE305nnn/GSE305228/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE305228GEOGSEfalseTDP2-mediated DNA repair regulates the dynamics of neuronal early response gene transcription and cortical neuron connectivityNeuronal activity induces topoisomerase IIb (TOP2B) to form DNA double strand breaks (DSBs) within the promoters of specific early response genes (ERGs), such as Fos, FosB, and Npas4, and these DSBs facilitate rapid ERG transcription. Yet how activity-induced DSBs are repaired and the significance of such mechanisms for neuronal function remain unclear. Here we show that the proteasome and the enzyme, tyrosyl-DNA phosphodiesterase 2 (TDP2), catalyze the initial processing of TOP2B-mediated DSBs in neurons. Knockdown of Tdp2 delayed the repair of neuronal activity-induced DSBs and prolonged the expression of ERGs in primary mouse cortical neurons, indicating that TDP2-mediated DNA repair is essential for the temporal control of ERG transcription. Deletion of Tdp2 in excitatory forebrain neurons caused DSB accrual and ERG overexpression, and these changes were associated with increased excitatory synaptic transmission and cortical circuit dysfunction. Mutations in TDP2 cause the disease, SCAR23 (spinocerebellar ataxia, autosomal recessive 23), which manifests predominantly with neurological abnormalities. We show that whereas proliferating cells possess redundant pathways to process TOP2B-mediated DSBs, these pathways are relatively inactive in postmitotic neurons. Together, these results underscore the neuroprotective roles of TDP2 and suggest that activity-induced DSBs could be relevant sources of DNA lesions for neurodegeneration.2026/08/12GSE305228GSM9166025GSM9166024GSM9166023GSM9166022GSM9166021GSM916602024247305228Mus musculus