Functional assessment of a kcnb1 knock-out zebrafish to model KCNB1-related neurodevelopmental and epileptic disorders

KCNB1 encodes the Kv2.1 potassium channel α-subunit. De novo pathogenic variants of KCNB1 with loss-of-function (LOF) properties have been associated with neurodevelopmental and epileptic disorders (DEE) diagnosed in early childhood. The study aims to characterize a knock-out (KO) zebrafish line targeting kcnb1 (kcnb1+/− and kcnb1−/− ). We examined the spatial expression of kcnb1, as well as phenotypic behavior, cellular, and electrophysiological activity of fish during early development stages. In wild-type larval zebrafish, kcnb1 was found in various regions of the central nervous system but was undetected in the KO model. Both kcnb1 +/− and kcnb1 −/− zebrafish displayed impaired swimming behavior and “epilepsy-like” features that persisted through embryonic and larval development, with variable severity. When exposed to the chemoconvulsant pentylenetetrazol (PTZ), mutant fish showed elevated locomotor activity and epileptiform-like electrographic activity. In addition, PTZ-exposed kcnb1 −/− larvae exhibited higher bdnf mRNA expression and activated c-Fos positive neurons in the telencephalon. In this KO model, neuronal circuits, muscle fibers and neuromuscular junction organization remained unaffected, including normal AchR cluster distribution, although a decreased AchE mRNA expression was observed. kcnb1 KO zebrafish develops early DEE-like phenotypes that affects neuronal functions. This study highlights the model’s relevance for investigating developmental neuronal signaling pathways in KCNB1 -related DEEs. ### Competing Interest Statement The authors have declared no competing interest.