Chapter 58 - In Utero Irradiation as a Model of Cortical Dysplasia

Abstract

In utero irradiation in rats is an animal model of human focal cortical dysplasia (FCD). Mechanistically it is an injury-based model of FCD and histologically it most closely resembles human FCD Type Ib according to current ILAE classifications. Pregnant female rats are exposed to 225 cGy external radiation on the 17th day of gestation (E17). The offsprings are delivered, nursed, and weaned normally. When studied as mature animals, the irradiated offsprings demonstrate microcephaly, diffuse CD, subcortical and periventricular heterotopia, heterotopic neurons in the hippocampus and agenesis or hypoplasia of the corpus callosum. Irradiated rats show increased susceptibility to seizures and some rats show spontaneous, recurrent seizures. Irradiated rats show a number of defects in learning and memory, some of which correlate with impaired long-term plasticity in the hippocampi of these animals. Irradiated rats show a significant loss of GABAergic interneurons in the affected neocortex. This results in reduced inhibition in neocortical pyramidal neurons. The surviving interneurons also show physiological impairment in the form of reduced excitatory drive and relative quiescence when spontaneous firing rates are examined. This model demonstrates that a single, nonlethal injury at a specific time point in cortical development can produce severe impairment in the inhibitory systems of the neocortex that persist into adulthood. This may have direct relevance for human disorders of cortical development that include some forms of human FCD and epilepsy.