Abstracts

Rationale: Animal studies show that prenatal exposure to high levels of corticosteroids results in sex-specific reprogramming of the brain leading to behavioral deficits and as well as to predisposition to autistic features. In this study, we investigated brain transcriptomic alterations in a model of infantile spasms consisting of prenatal betamethasone exposure and postnatal trigger of spasms using N-methyl-D-aspartic acid (NMDA) in the hypothalamic arcuate nucleus, identified by imaging as one of the spasm-controlling structures in this model. Our Genomic Fabric Paradigm (GFP) represents a transformative research approach for enhanced understanding of the brain transcriptomic alterations in disease, treatment and recovery. The genomic fabric of a particular synapse set is the structured transcriptome associated with the most interconnected and stably expressed gene network responsible for that type of neurotransmission. GFP refines the description of functional pathways by selecting the most prominent genes and determining their networking. Moreover, it quantifies the remodeling of functional pathways and their interplay in disease and recovery in response to a treatment. Methods: We profiled the whole transcriptomes in hypothalamic arcuate nuclei of 20 male rats (5 experimental groups) using Agilent rat gene expression two-color 4x44k microarrays to determine the remodeling of the genomic fabrics responsible for the glutamatergic, GABAergic, dopaminergic, cholinergic and serotonergic transmission in the model of infantile spasms and recovery following different treatments. The rats were prenatally (G15) exposed to betamethasone or saline followed by repeated administration of NMDA on postnatal days (P) 12, 13 and 15, which triggered the spasms. Pups were treated with either ACTH, PMX53 (a potent C5ar1 antagonist) or vehicle on P12, 13 and 14 to determine what effects each treatment had on the transcriptome recovery. The normalized microarray results were deposited and are publically accessible in http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE81061. Results: Using GFP, we found that prenatal betamethasone priming had substantial consequences on the topology of the genomic fabrics in all investigated synapse sets (illustrated in Fig. 1) and that the NMDA-induced spasms strongly exacerbated the remodeling of these fabrics. However, ACTH treatment, which significantly impoves outcome in infantile spasms in human as well as in this model, recovered 49% of the normal transcriptome in the hypothalamic arcuate nucleus. Surprisingly, PMX53 treatment recovered as much as 64% of the normal transcriptome despite having no significant effect on outcome of spasms in the model. Conclusions: We found significant improvements in remodeling of transcriptome after both treatments (ACTH and PNX53), however only ACTH was effective in suppression of spasms. We speculate that PMX53, while ineffective in suppression of spasms, might improve other impairments associated with the spasms such as cognitive function. Funding: CURE Infantile Spasms Research Initiative