Abstracts

Rationale: During postnatal neuronal migration in the rodent cortex, a majority of neurons are in their zone beneath the molecular zone as controlled by release of Reelin. Neuronal migration disorders, however, are common outcomes of spontaneous genetic mutations, such as with the Reeler mouse. Our experiments have used prenatal radiation (at E17) to induce a dramatically different form of neuronal disorientation that includes several cellular mechanisms persisting long after birth.Methods: 24 pregnant rats were given whole body gamma radiation at day E17 with 145 Rads, and the littermates were sacrificed at different development days (P1, P4, P8, P16, and P24). Age-matched controls were sacrificed the same days. After their brains were harvested and fixed in 4% PFA, they were cryosectioned into 30um sections for subsequent staining, which was batch processed for CV and dual IF staining for both radiated and control groups.Results: Although the cytoplasmic protein in the radiated cortices continued to grow at the same rate as the age-matched control pups, detailed studies of the Reelin pathway's effects on lipoprotein receptors, excitatory receptors, and intracellular signaling kinases showed that prenatal radiation induced significant upregulations that persisted for weeks postnatally. In all dual IF, the radiated cortices showed increased colocalization of lipoprotein receptors (ApoER2, VLDLR), which would be expected (see Figure 1). However, these lipoprotein receptors also strongly colocalized with the NMDA receptor subunit, NR2A/B (see Figure 2), which has been suggested by Beffert et al.,2005 as a mechanism for enhancing excitatory synaptic transmission.Conclusions: To determine mechanisms for cortical disorganizations, we used prenatally radiated rodents and studied the postnatal development and maintenance of cellular mechanisms that contribute to the unique neuron clusters and abnormal synaptic connections. We conclude that prenatal radiation upregulates most of the critical steps in the Reelin pathway, disturbing normal cortical lamination and eventually developing aberrant axonal plexuses that may lead to seizure susceptibility.