ROLE OF CDR1AS AND MIR-7 IN REGULATING SYNAPTIC FUNCTION AND ITS CONSEQUENCE ON SEIZURE PROGRESSION IN HUMAN NEURONAL MODEL SYSTEMS

CDR1as is a circular RNA (circRNA) enriched in neurons that directly interacts with a microRNA (miRNA), miR-7, within a tightly regulated non-coding RNA network. In mouse models, Cdr1as buffers miR-7 activity, influencing glutamatergic transmission and neuronal connectivity. Additionally, Cdr1as expression is altered by external stressors, and its interacting miRNA, mir-7, has several predicted synaptic targets, implicating this network in activity-related disorders, such as epilepsy. However, research in human neuronal models is limited.
This project aims to investigate how CDR1as-miR-7 interaction affects human neuronal function under seizure-like stress using human-induced pluripotent stem cell (hiPSC)-derived forebrain neurons and organoids. CDR1as knockout (KO) and control (WT) hiPSC lines were generated, differentiated into neurons and organoids, and characterised for their baseline phenotypes using transcriptomics and imaging. This was followed by exposing KO and WT neurons to seizure-inducing stimulants for different durations, resulting in dynamic changes in CDR1as expression over time in WT neurons. These changes caused a transient increase of miR-7 in WT over KO at a specific timepoint, aligning with stronger repression of predicted miR-7 targets in these WT neurons. Additionally, transcriptomic profiling revealed coordinated changes linked to synapse organisation and cytoskeletal dynamics in KO, consistent with the hypothesis of altered network adaptation in the absence of CDR1as.
Mapping miR-7 targets under these conditions will reveal the candidates through which KO-associated changes manifest. Together, this will provide mechanistic insight into how CDR1as-miR-7 axis contributes to modulating neuronal function during epileptogenic-like stress, identifying potential therapeutic targets to resolve activity-related disorders.