Modeling central nervous system disorders in zebrafish: Novel insights into pathophysiology and therapeutic discovery
Xin Meng, Lan Yang, Zi Liao, Feiyue Sun, Meng Su, Zhigang Mei
Abstract
Central nervous system (CNS) disorders present a profound global health burden, yet therapeutic progress is frequently impeded by their mechanistic complexity, the restrictive nature of the blood-brain barrier (BBB), and the limitations of traditional mammalian models. The zebrafish ( Danio rerio ) has emerged as a powerful vertebrate model system uniquely positioned to surmount these obstacles. Its genetic tractability and the conserved principles of its neurovascular development provide an unparalleled platform for dissecting complex disease pathways in vivo. The optical transparency of zebrafish larvae, in particular, enables real-time, high-resolution imaging of dynamic cellular processes, such as neuroinflammation and neurovascular unit dysfunction, offering mechanistic insights unattainable in other models. Furthermore, key physiological traits—including external fertilization for high-throughput screening and exceptional hypoxia tolerance for robust ischemic stroke modeling—make zebrafish an ideal tool for both fundamental research and preclinical drug discovery. This review synthesizes the pivotal contributions of the zebrafish model to our understanding of a wide spectrum of CNS disorders, and highlights its expanding role in accelerating the identification of novel therapeutic strategies. • Sensitive zebrafish gills expand drug delivery options with evolutionarily conserved brain development. • Hypoxia tolerance and embryo transparency enable noninvasive central nervous system disease modeling. • Whole-organism screening in zebrafish expedites discovery of neurotherapeutics.