Altered Cerebral Cortical Gyrification in Ferrets with Neonatal Exposure to the Bacterial Endotoxin, Lipopolysaccharide.

Abstract

Lipopolysaccharide (LPS) is a bacterial endotoxin that induces innate immune responses. The present study aimed to elucidate alterations in cerebral cortical surface morphology induced by neonatal exposure to LPS using gyrencephalic ferrets. Male ferret pups received a subcutaneous injection of LPS (500 µg/g of body weight) on Postnatal Day (P)6 and P7. Furthermore, EdU and BrdU were administered on P5 and P7, respectively, to label postproliferative and proliferating cells that were exposed to LPS in the late stage of cortical neurogenesis. On P20 when the primary sulci and gyri had formed, MRI-based morphometry revealed an anterior shift in sulcal infolding in the medial and dorsolateral cortices of LPS-exposed ferrets. Immunofluorescence analysis showed that LPS increased the density of BrdU-labeled cells and reduced their apoptosis, as indicated by cleaved caspase-3 (cCasp3) immunostaining, in the outer stratum of the lateral sulcus located on the parietal association cortex. Furthermore, cCasp3 immunostaining of EdU-labeled cells was enhanced in the presylvian and lateral sulci located in the prefrontal and parietal association cortices, respectively, but was reduced in the coronal sulcus and gyrus located on the primary motor cortex in LPS-exposed ferrets. This study is the first to elucidate the effect of bacterial components on cerebral cortical sulcogyrogenesis, which is involved in the pathogenesis of neurodevelopmental disorders. Such altered sulcal topology may be attributed to a region-related effect on cortical neuron apoptosis in the medial and dorsolateral cortices caused by neonatal LPS exposure.