Abstract
Mutations in the RBFOX1 gene are associated with psychiatric disorders but how RBFOX1 influences psychiatric disorder vulnerability remains unclear. Recent studies showed that RBFOX proteins mediate the alternative splicing of PAC1, a critical HPA axis activator. Further, RBFOX1 dysfunction is linked to dysregulation of BDNF/TRKB, a pathway promoting neuroplasticity, neuronal survival, and stress resilience. Hence, RBFOX1 dysfunction may increase psychiatric disorder vulnerability via HPA axis dysregulation, leading to disrupted development and allostatic overload. To test this hypothesis, we generated a zebrafish rbfox1 loss-of-function (LoF) line and examined behavioural and molecular effects during development. We found that rbfox1 LoF mutants exhibited hyperactivity, impulsivity and heightened arousal, alongside alterations in proliferation - traits associated with neurodevelopmental and stress-related disorders. In adults, loss of rbfox1 function led to decreased fertility and survival, consistent with allostatic overload. At the molecular level, at larval stages rbfox1 LoF disrupted the expression of bdnf, trkb2, pac1a-hop and HPI axis genes. Pharmacological intervention targeting TRKB restored HPI axis and bdnf/trkb2 gene expression. In adults, dysregulation of bdnf/trkb2 and HPI axis genes was only seen following acute stress exposure. Our findings revealed a fundamental role for RBFOX1 in integrating stress responses through its regulation of BDNF/TRKB and neuroendocrine signalling. By uncovering how RBFOX1 modulates stress adaptation from development to adulthood, our study provides novel insights into the molecular basis of stress resilience and psychiatric disease vulnerability, suggesting RBFOX1 loss predisposes to psychiatric diseases through HPA axis hyperactivation during development, impairing adaptation and heightening vulnerability to allostatic overload in later life.