IMBALANCES IN EXCITATORY AND INHIBITORY SIGNALLING AND ALTERED NEURAL CIRCUIT DYNAMICS IN <EM>RBFOX1</EM> MUTANT ZEBRAFISH

The splicing factor RBFOX1 exerts pleiotropic effects on numerous neurodevelopmental and psychiatric disorders. Previous studies by our group in two zebrafish lines showed that mutations in rbfox1 lead to hyperactivity, increased thigmotaxis, and social impairments. However, the biological mechanisms underlying these behavioural changes remain unclear. In this study, we investigated the effects of rbfox1 on neurotransmission and neural activity during development and adulthood using the rbfox1^sa15940 mutant zebrafish line. We observed multifaceted disruptions in neurotransmission and neural activity in the mutant zebrafish. UPLC/MS-MS analyses revealed lower basal levels of the neurotransmitters serotonin, dopamine, GABA, and glutamate in the telencephalon and diencephalon. In vivo whole-brain imaging showed altered neuronal activity across different brain regions. At the single-cell level, we detected increased numbers of active neurons in the midbrain and medulla oblongata, while in the cerebellum the fraction of single-cell spikes occurring in bursts was significantly higher. At the population level, we observed a higher collective bursting rate in the cerebellum, midbrain and medulla oblongata, along with a shorter duration of collective bursts in the cerebellum and forebrain of mutant fish. Connectivity analyses further showed brain-wide network effects in the rbfox1 mutant zebrafish. Together, these results indicate disruptions in neural circuit development, which are already present in larval stages, resulting in an imbalance of excitatory and inhibitory signalling persisting into adulthood. Our findings highlight the crucial role of rbfox1 in regulating a gene network and the intricate interactions between neurotransmission and neuronal activity that contribute to neurodevelopmental and psychiatric disorders.