ACTH and PMX53 recover synaptic transcriptome alterations in a rat model of infantile spasms

Dumitru A Iacobaş,Jana Velíšková,Tamar Chachua,Libor Velíšek,Sanda Iacobaş,Melissa J Benson,Karin Borges

doi:10.1038/s41598-018-24013-x

Abstract

We profiled the gene expression in the hypothalamic arcuate nuclei (ARC) of 20 male and 20 female rats to determine the infantile spasms (IS) related transcriptomic alteration of neurotransmission and recovery following two treatments. Rats were prenatally exposed to betamethasone or saline followed by repeated postnatal subjection to NMDA-triggered IS. Rats with spasms were treated with ACTH, PMX53 or saline. Since ACTH, the first line treatment for IS, has inconsistent efficacy and potential harsh side effects, PMX53, a potent complement C5ar1 antagonist, was suggested as a therapeutic alternative given its effects in other epilepsy models. Novel measures that consider all genes and are not affected by arbitrary cut-offs were used, in addition to standard statistical tests, to quantify regulation and recovery of glutamatergic, GABAergic, cholinergic, dopaminergic and serotonergic pathways. Although IS alters expression of ~30% of the ARC genes in both sexes the transcriptomic effects are 3× more severe in males than their female counterparts, as indicated by the Weighted Pathway Regulation measure. Both treatments significantly restored the ARC neurotransmission transcriptome to the non-IS condition with PMX53 performing slightly better, as measured by the Pathway Restoration Efficiency, suggesting these treatments may reduce autistic traits often associated with IS.

Highlights

Infantile spasms (IS; a term often interchangeably used with West syndrome) occur in 1:3200–1:3400 of live births
Neuroinflammation, including that regulated via innate immune complement activation, represents a significant process involved in epilepsy[9,10,11] and ASD12
Using gene expression microarrays and advanced analytical tools, our report, on the hypothalamic arcuate nucleus (ARC) of young male and female rats, provides additional findings related to infantile spasms (IS)-associated transcriptomic changes and recovery in response to two different treatments

Summary

Introduction

Infantile spasms (IS; a term often interchangeably used with West syndrome) occur in 1:3200–1:3400 of live births. We profiled the gene expression in the ARC of our model under several conditions following repeated spasms with and without ACTH or PMX53 treatments in primed animals (Fig. 1A,B).

Results

Conclusion