TDP2-mediated DNA repair regulates the dynamics of neuronal early response gene transcription and cortical neuron connectivity (Figure S1 & S2)

However, mechanisms that repair activity-induced DSBs and their significance for neuronal function remain ill-defined. Here we report that depletion of tyrosyl-DNA phosphodiesterase 2 (TDP2) in cultured mouse cortical neurons delays the repair of TOP2B-mediated DSBs and prolongs ERG expression following neuronal stimulation.

Deleting Tdp2 in excitatory forebrain neurons in vivo caused DSB accrual, ERG overexpression, and increased excitatory synaptic transmission and cortical circuit dysfunction. Whereas proliferating cells utilize alternative pathways to process TOP2B-mediated DSBs, we find that such mechanisms are relatively inactive in postmitotic neurons. Overall, these results indicate that TDP2-mediated DNA repair is crucial for the temporal control of ERG transcription and suggest that defective repair of activity-induced DSBs could underlie neurological abnormalities in individuals with TDP2 mutations.