DNA damage during early neurogenesis impairs interneuron migration without altering their ultimate cortical positioning

Proper interneuron migration and distribution are essential for optimal brain function. Disruptions of this process can impair the excitation/inhibition balance, leading to neurodevelopmental disorders. As such, ionizing radiation poses a particular risk to the developing brain, as it can lead to excessive fetal DNA damage and subsequent microcephaly. Although research on radiation-induced microcephaly has mainly focused on glutamatergic excitatory neurons, the impact on GABAergic interneurons is equally crucial. Understanding potential disruptions is essential for comprehensive insights into the excitation/inhibition balance and implications for brain development. Here, ionizing radiation at embryonic day (E)11, an early stage of neurogenesis, was used to induce DNA damage in mouse fetuses. We assessed the DNA damage response in the cortex compared to medial ganglionic eminence (MGE), and interneuron migration in living brain slices and MGE explants. Additionally, we evaluated susceptibility to pentylenetetrazole-induced epileptic seizures in irradiated offspring. Irradiation induced DNA damage, cell cycle arrest and a significant increase in apoptosis in the MGE. At E13, a pivotal time point of interneuron migration, impaired migration of interneurons from MGE to neocortex was observed in irradiated brain slices, and confirmed in MGE explants. However, despite an overall reduction in cortical parvalbumin and somatostatin interneurons after birth, their overall positioning and distribution remained unchanged, with no impact on seizure susceptibility. Overall, despite the lack of impact on the excitation/inhibition balance from radiation exposure during neurodevelopment, it indeed results in significant DNA damage and substantial disruption in interneuron migration.