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.

Details

Title
ACTH and PMX53 recover synaptic transcriptome alterations in a rat model of infantile spasms
Author
Iacobaş, Dumitru A 1 ; Chachua, Tamar 2 ; Iacobaş, Sanda 3 ; Benson, Melissa J 4 ; Borges, Karin 5 ; Velíšková, Jana 6 ; Velíšek, Libor 7 

 Center for Computational Systems Biology, Prairie View AM University, Prairie View, TX, USA; D.P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, NY, USA 
 New York Medical College School of Medicine, Department of Cell Biology and Anatomy, Valhalla, NY, USA 
 New York Medical College School of Medicine, Department of Pathology, Valhalla, NY, USA 
 New York Medical College School of Medicine, Department of Cell Biology and Anatomy, Valhalla, NY, USA; University of Queensland, School of Biomedical Sciences, Brisbane, Australia 
 University of Queensland, School of Biomedical Sciences, Brisbane, Australia 
 New York Medical College School of Medicine, Department of Cell Biology and Anatomy, Valhalla, NY, USA; New York Medical College School of Medicine, Department of Neurology, Valhalla, NY, USA; New York Medical College School of Medicine, Department of Obstetrics and Gynecology, Valhalla, NY, USA 
 New York Medical College School of Medicine, Department of Cell Biology and Anatomy, Valhalla, NY, USA; New York Medical College School of Medicine, Department of Neurology, Valhalla, NY, USA; New York Medical College School of Medicine, Department of Pediatrics, Valhalla, NY, USA 
Pages
1-11
Publication year
2018
Publication date
Apr 2018
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2023717918
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.