Differential gene expression profiling implicates altered network development in rat postnatal day 4 cortex following 4-Methylimidazole (4-MeI) induced maternal seizures

Abstract

Compromised maternal health leading to maternal seizures can have adverse effects on the healthy development of offspring. This may be the result of inflammation, hypoxia-ischemia, and altered GABA signaling. The current study examined cortical tissue from F2b (2nd litter of the 2nd generation) postnatal day 4 (PND4) offspring of female Harlan SD rats chronically exposed to the seizuregenic compound, 4-Methylimidazole (0, 750, or 2500 ppm 4-MeI). Maternal seizures were evident only at 2500 ppm 4-MeI. GABA related gene expression as examined by qRT-PCR and whole genome microarray showed no indication of disrupted GABA or glutamatergic signaling. Canonical pathway hierarchical clustering and multi-omics combinatory genomic (CNet) plots of differentially expressed genes (DEG) showed alterations in genes associated with regulatory processes of cell development including neuronal differentiation and synaptogenesis. Functional enrichment analysis showed a similarity of cellular processes across the two exposure groups however, the genes comprising each cluster were primarily unique rather than shared and often showed different directionality. A dose-related induction of cytokine signaling was indicated however, pathways associated with individual cytokine signaling were not elevated, suggesting an alternative involvement of cytokine signaling. Pathways related to growth process and cell signaling showed a negative activation supporting an interpretation of disruption or delay in developmental processes at the 2500 ppm 4-MeI exposure level with maternal seizures. Thus, while GABA signaling was not altered as has been observed with maternal seizures, the pattern of DEG suggested a potential for alteration in neuronal network formation.