Authors :
Theresa Auer, BSc, MSc – University College Dublin
Morten Veno, PhD – University of Aarhus
Rory Johnson, PhD – University College Dublin
David Henshall, PhD – Royal College of Surgeons Ireland
Cristina Reschke, PhD – Royal College of Surgeons Ireland
Presenting Author: Gary Brennan, PhD – University College Dublin
Rationale: Large-scale changes in epigenetic-mediated regulation of gene expression triggered by a precipitating brain insult may drive the development of temporal lobe epilepsy (TLE).
Although long non-coding RNAs (lncRNAs) have emerged as key modulators of RNA processing and transcriptional control, their functional involvement in epilepsy pathogenesis remains largely unexplored. Here, we perform the first comprehensive profiling of lncRNAs during epileptogenesis and assess their utility as novel drug targets.
Methods: To study lncRNA dysregulation, Next Generation Sequencing was performed on hippocampal tissue collected during epilepsy development in kainic acid-induced mouse models of TLE. LncRNAs with high pro-epileptogenic potential were predicted using bioinformatic tools and the anticonvulsant effect of their targeted inhibition was tested in the pentylenetetrazol-induced acute seizure model. Long term assessment of lncRNA-based interventions were assessed in the intra-amygdala kainic acid model using long term continuous EEG recordings and a battery of cognitive behavioral assessments. Mechanism of action of lncRNAs were assessed using a combination of proteomics and immunostaining.
Results: Transcriptomic analysis revealed significant changes in many lncRNAs, several of them known for their importance during development, in plasticity and cell death. Based on various characteristics including the expression level, expression change and inter-species conservation, we selected five promising lncRNA candidates and successfully achieved their target-specific, long-lasting downregulation
in vivo using antisense oligonucleotides (ASOs). In a pre-treatment study we found that ASO-mediated lncRNA inhibition had significant anticonvulsant effects. Similarly, in long term assessments ASO-targeting of lncRNAs improved epilepsy-associated learning and memory deficits and improved seizure outcomes.
Conclusions: Epileptogenesis is characterized by extensive lncRNA dysregulation, which likely contributes to many epileptogenic processes. This renders lncRNAs promising targets for the development of therapeutic and/or preventative treatment approaches.
Funding: This research is funded by grants from UCD's Ad Astra funds and the Health Research Board with Epilepsy Ireland under the Health Research Charities Ireland Funding Mechanism (HRCI-HRB-2022-034).