TDP2-mediated DNA repair regulates the dynamics of neuronal early response gene transcription and cortical neuron connectivity.

TDP2-mediated DNA repair is essential for timely regulation of early response gene transcription in cortical neurons, with Tdp2 deletion causing ERG overexpression and circuit dysfunction.

• Why it matters: Understanding how neurons repair activity-induced DNA double-strand breaks is critical because defective repair may contribute to neurological disorders, yet the mechanisms in postmitotic neurons are poorly understood.
• What they did: The study used cultured mouse cortical neurons and in vivo models to deplete or delete Tdp2, observing delayed repair of TOP2B-mediated DSBs and prolonged ERG expression after neuronal stimulation.
• The result: Loss of TDP2 function led to DSB accumulation, increased excitatory synaptic activity, and cortical circuit abnormalities, highlighting TDP2’s role in controlling ERG transcription and neuronal connectivity.