The DEC2‐SCN2A Axis is Essential for the Anticonvulsant Effects of Cannabidiol by Modulating Neuronal Plasticity

Abstract Impairment of neuronal plasticity is involved in a spectrum of neurological disorders such as epilepsy, yet its regulatory mechanisms remain incompletely understood. Here, it is reported that the basic helix‐loop‐helix transcription factor DEC2 serves as a pivotal regulator of both neuronal plasticity and epileptogenesis through its repression of sodium voltage‐gated channel alpha subunit 2 (SCN2A). Knockdown of DEC2 in hippocampal neurons elevates intrinsic excitability and synaptic transmission, exacerbating seizure susceptibility and severity. Conversely, overexpression of DEC2 in hippocampus reduces intrinsic excitability and synaptic transmission, ultimately decreasing seizure susceptibility. Mechanistically, DEC2 functions as a transcriptional repressor of Scn2a by directly binding class B E‐boxes (CACGTG) in its promoter. Additionally, DEC2 forms complexes with myoblast determination protein 1 (MYOD1) and occupies the CAGCTG E‐boxes within the Scn2a promoter; however, this interaction does not affect Scn2a transcription in vivo. These findings also reveal that cannabidiol (CBD) can modulate the DEC2‐SCN2A axis. Notably, CBD predominantly enhances DEC2's direct transcriptional repression of SCN2A. In summary, this study identifies DEC2 as a critical regulator of neuronal plasticity in epilepsy progression, suggesting a novel therapeutic pathway for epilepsy treatment.