Multi-omics analysis of a drug-induced model of bipolar disorder in zebrafish

Emerging studies demonstrate that inflammation plays a crucial role in the patho-genesis of bipolar disorder (BD), but the underlying mechanism remains largely un-clear. Given the complexity of BD pathogenesis, we performed high-throughput multi-omic profiling (metabolomics, lipidomics, and transcriptomics) of the BD ze-brafish brain to comprehensively unravel the molecular mechanism. Our research proved that in BD zebrafish, JNK-mediated neuroinflammation altered metabolic pathways involved in neurotransmission. On one hand, disturbed metabolism of tryptophan and tyrosine limited the participation of the monoamine neurotrans-mitters serotonin and dopamine in synaptic vesicle recycling. On the other hand, dysregulated metabolism of the membrane lipids sphingomyelin and glycerophos-pholipids altered the synaptic membrane structure and neurotransmitter recep-tors (chrna7, htr1b, drd5b, and gabra1) activity. Our findings revealed that distur-bance of serotonergic and dopaminergic synaptic transmission mediated by the JNK inflammatory cascade was the key pathogenic mechanism in a zebrafish model of BD, provides critical biological insights into the pathogenesis of BD.

Automated summary

Emerging studies showed that inflammation is crucial in the pathogenesis of bipolar disorder, but the underlying mechanism is unclear. By analyzing different -omics data, we unraveled the comprehensive molecular mechanism in the zebrafish model of BD. We found that JNK-mediated neuroinflammation altered metabolic pathways involved in neurotransmission, leading to disturbed serotonergic and dopaminergic synaptic transmission.