NEAT1 Promotes Epileptogenesis in Tuberous Sclerosis Complex

The primary neurological manifestations of tuberous sclerosis complex (TSC) are intractable epilepsy and intellectual impairment. Current treatment outcomes remain limited. Investigating the role of the epigenetic long non-coding RNA NEAT1 in TSC-related epilepsy and cognition is essential. RNA sequencing analysis of clinical tissue samples revealed that NEAT1 is differentially expressed in epileptogenic versus non-epileptogenic tubers and enriched in the PI3K-AKT signaling pathway. To prove and further investigate the functional role suggested by the earlier transcriptomic and pathway enrichment analyses, NEAT1-overexpression and NEAT1-knockdown TSC2 conditional knockout (CKO) mouse models, as well as TSC2-KO cell models, are established. In vivo experiments demonstrated that NEAT1 knockdown reduced seizure frequency and improved spatial learning and working memory. Cellular analyses in TSC model further revealed that NEAT1 significantly regulates the PI3K/AKT/mTOR signaling pathway, neurotransmitter receptor balance, and outward potassium currents. Specifically, NEAT1 overexpression excessively activated the mTORC1 signaling, leading to changes in 4E-BP1 and S6K and abnormal cell proliferation. Moreover, NEAT1 overexpression contributed to an imbalance in excitatory neurotransmitter receptors and outward potassium currents, resulting in neuronal hyperexcitability, whereas NEAT1 knockdown has the opposite effect. This study provides new insights into the transcriptional regulation of TSC-related epilepsy, highlighting the therapeutic potential of NEAT1.