Circadian changes in the hippocampal transcriptome in an animal model of mesial temporal lobe epilepsy
Abstract number :
1.45
Submission category :
1. Basic Mechanisms / 1E. Models
Year :
2022
Submission ID :
2233026
Source :
www.aesnet.org
Presentation date :
12/3/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:29 AM
Authors :
Mani Sandhu, MD – University of Iowa; Mani Sandhu, MD – Yale University; Roni Dhaher, PhD – Yale University; Shaun Gruenbaum, MD, PhD – Yale University; Sonia Seth, BA – Yale University; Raaisa Raaisa, PhD – Yale University; sameet Mehta, PhD – Yale University; Tamara Jafar, BA – Yale University; Milena Pavlova, MD – Harvard University; Stephen Pincus, PhD – Yale University; Dennis Spencer, MD – Yale University; Hitten Zaveri, PhD – Yale University; Tore Eid, MD, PhD – Yale University
This is a Late Breaking abstract
Rationale: Several genes undergo circadian-like (~24-hour) changes preferentially in the epilepsy brain, suggesting possible causal relationships between the genome/proteome and seizure rhythmicity. Whether these oscillations are altered in epileptic regions is largely unknown. Here, we used a translational model of mesial temporal epilepsy to study circadian-like changes in the transcriptome in the epilepsy vs. control hippocampus.
Methods: Eighteen rats were infused with the glutamine synthetase inhibitor methionine sulfoximine (MSO) in the right hippocampus to create epilepsy, and 18 rats were infused with phosphate buffered saline (PBS) to serve as controls. Six animals (3 MSO and 3 PBS) were euthanized every 4 hours, at 24:00, 4:00, 8:00, 12:00, 16:00, 20:00. The right hippocampus was removed and snap frozen in liquid nitrogen. RNA was extracted and sequenced. The Jonckheere-Terpstra and Kendall (JTK) method was used to determine the rhythmicity of gene transcripts over the 24-hour cycle.
Results: Using the JTK algorithm, we identified 1,195 gene transcripts with 24-hour rhythmicity in the epilepsy hippocampus vs. 1,091 transcripts in control. Only 185 (~15%) of these transcripts were identified in both groups, suggesting a different rhythmic transcriptome landscape between epilepsy and controls. Forty-one of the oscillating transcripts in the epilepsy brain were associated with established circadian pathways vs. 37 in control. Additional rhythmic transcripts unique to the epilepsy brain included: adenosine A1 receptor (adora1), CCAAT enhancer-binding protein beta (cebpb), cryptochrome circadian regulator 2 (cry2), DEAD-box helicase 5 (ddx5), dopamine receptor D1 (drd1), F-box and WD repeat domain containing 11 (fbxw11), hypoxia-inducible factor 1 subunit alpha (hif1a), heterogeneous nuclear ribonucleoprotein U (hnrnpu), nocturnal (noct), protein phosphatase 1 catalytic subunit gamma (ppp1cc), prokineticin receptor 2 (prokr2), paraspeckle component 1 (pspc1), RAR related orphan receptor B (rorb), serpin family E member 1 (serpine1), splicing factor 3a subunit 3 (sf3a3), splicing factor proline and glutamine-rich (sfpq), salt inducible kinase 1 (sik1), SUV39H2 histone lysine methyltransferase (suv39h2), TATA-box binding protein associated factor 1 (taf1), DNA topoisomerase I (top1), and ubiquitin-specific peptidase 7 and 46 (usp7 and usp46). Seventeen of the oscillating transcripts in the epilepsy brain were associated with GABAergic pathways vs. 23 in control.
Conclusions: The epilepsy brain features several gene transcripts that oscillate differently during the 24-hour cycle than control. This knowledge is expected to enhance our understanding of circadian seizure vulnerability and result in novel chronotherapeutic interventions for epileptic seizures.
Funding: NIH/NINDS NS109734
Basic Mechanisms