Aims: Large-scale changes in epigenetic-mediated regulation of gene expression is known to drive the development of temporal lobe epilepsy (TLE) after a precipitating brain insult. Although long non-coding RNAs (lncRNAs) are key modulators of RNA processing, their functional involvement in epilepsy pathogenesis remains largely unexplored. Here, we perform the first comprehensive profiling study 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 advanced bioinformatic tools and the anticonvulsant effect of their targeted inhibition was tested in the pentylenetetrazol-induced acute seizure model. We are now investigating anti-epileptogenic potential using in vivo EEG recording combined with behavioural testing. Results: Transcriptomic analysis revealed significant changes in numerous 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 could show that ASO-mediated lncRNA inhibition exerts significant anticonvulsant effects. These oligonucleotides are now being used to investigate the long-term, disease-modifying potential of targeting dysregulated lncRNAs with encouraging preliminary results. 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.