Transcriptomic Profile of Genetically-epilepsy Prone Rats (GEPRs)
Abstract number :
3.285
Submission category :
3. Neurophysiology / 3F. Animal Studies
Year :
2024
Submission ID :
574
Source :
www.aesnet.org
Presentation date :
12/9/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Carolina Campos-Rodriguez, PhD, MSc – Georgetown University
David McFall, PhD/MDc – Georgetown University
Brianna Fulton, MSc – Georgetown University
Sean Quinlan, PhD – Georgetown University
Patrick Forcelli, PhD – Georgetown University
Author: Prosper N'Gouemo, PhD – Howard University College of Medicine
Rationale: The Genetically Epilepsy Prone Rats (GEPR-3) strain was originally characterized in the 1960s, and displays brainstem-dependent generalized tonic-clonic seizures in response to high intensity noise (audiogenic stimulation). For over half a century, this model has been used in studies of seizure circuitry, pharmacotherapy, and comorbidities. Despite its long use, the genetic basis of seizures in the GEPRs remains poorly understood. To address this gap we performed bulk RNA sequencing of the inferior colliculus (IC), the site of seizure origin in GEPR-3s
Methods: We compared the transcriptomic profile of the IC in female animals (GEPR-3 and Sprague-Dawley) subjected to audiogenic stimulation to animals that were not subjected to audiogenic stimulation (n=6 per group). Data were processed using standard RNAseq bioinformatic pipelines, including gene set enrichment analysis. In follow up studies, we examined a subset of transcripts in the superior colliculus (SC), a site that is engaged by audiogenic seizures and from which stimulation can suppress AGS.
Results: Audiogenic stimulation in wild type rats resulted in 254 differentially express transcripts. By contrast, only 58 transcripts were differentially expressed between stimulated and non-stimulated GEPR-3s. 172 transcripts were differentially expressed between stimulated GEPRs and stimulated wild type animals. Notably, 407 transcripts were differentially expressed between non-stimulated GEPRs and non-stimulated sham animals. Gene set enrichment revealed KEGG pathways (including neuroactive ligand-receptor interactions and calcium signaling pathway) were significantly enriched in both GEPR stimulated and non-stimulated conditions relative to wild type controls. From the neuroactive-ligand receptor interaction pathway, we chose a subset of biologically interesting targets, including GABA-A receptors, nicotinic receptors, ionotropic glutamate receptors, and purinergic receptors for further validation.
Conclusions: This study provides new insights into the transcriptomic differences between WT and GEPR rats both with and without AGS in the hopes of identifying useful therapeutic targets. Comparing WT- and GEPR-sham rats uncovered pathways that predispose GEPRs to seizures (neurotropic ligand-receptor interactions), whereas comparisons between GEPR-sham and GEPR-stim rats highlight changes as a result of seizures.
Funding: R01 NS097762-07 to Patrick Forcelli
NIH NIGMS T32 GM142520 to Dave McFall
Neurophysiology