Epidemiological studies as well as animal experiments have helped us understand some of the possible dangers of exposure to ionizing radiation. Particularly with regards to the central nervous system (CNS), week 8-15 and to a lesser extent week 16-25 of human pregnancy has been defined as the most radiosensitive period. By week 8, the development of the major organs has been completed, while the CNS is still undergoing key developmental processes such as neuronal proliferation, migration and differentiation, which explains its high sensitivity to radiation-induced damage. To better understand these radiation-induced defects, animal studies have proven extremely helpful, but there are still a lot of knowledge gaps and questions remaining. For instance, while most research has focused on excitatory neurons, data about possible radiation-induced changes in inhibitory interneurons are scarce. Yet, these types of neurons play an indispensable role in brain development, maturation and wiring of the brain, and are importantly involved in cognition. Strikingly, studies of in utero exposed atomic bomb survivors have demonstrated an increased occurrence of seizures and epilepsy, defined by a hyper-excitability of the neuronal network and a concomitant imbalance in inhibitory signaling. Furthermore, the cortical dysplasia model frequently used to investigate the cause and treatment of epileptic seizures can be attained through prenatal exposure to a high radiation dose. Hence, it is imperative to perform a more in-depth investigation on the inhibitory network following exposure to different doses of radiation, which will help in our understanding of the excitation/inhibition balance following prenatal irradiation, and inform on possible long-lasting complications that might include (non-convulsive) seizures, attention deficits, working memory decline or psychiatric disorders. This will in turn help to better inform oncologists and to ensure the most optimal treatment plan for pregnant cancer patients.
To tackle this unprecedented research question, we first set out to investigate the sensitivity of the in utero irradiated brain to induce seizures, by exposing mouse embryos to low (0.1 Gy) and high (1.0, 2.0 Gy) X-ray doses. Furthermore, we will investigate the development of inhibitory interneurons in mouse embryos by studying interneuron proliferation, migration and differentiation, and by following these cells until they reach their final destination in the postnatal cortex (integration and synapse formation). Next, we aim to investigate long-lasting functional defects that are associated with a defective inhibition, through the investigation of interneuron functionality, synaptic outputs and a possible imbalance in excitation/inhibition. Finally, the identification of differentially expressed genes (at RNA and protein levels) in isolated interneurons following irradiation will help to clarify the underlying mechanisms for the observed radiation-induced defects and evoked seizures.