rbfox1 loss of function in zebrafish leads to dysregulation in bdnf/trkb2 and pac1a expression resulting in HPI axis hyperactivation, altered stress response and allostatic overload

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. rbfox1 LoF mutants exhibited hyperactivity, impulsivity and hyperarousal, and alterations in proliferation, with adults also showing decreased fertility and survival, traits associated with allostatic overload. In larvae, rbfox1 LoF disrupted expression of pac1a-hop, bdnf, trkb2, and HPI axis genes. HPI axis and bdnf/trkb2 gene expression was restored after chronic TRKB agonist/antagonist treatment. In adults, bdnf/trkb2 and HPI axes dysregulation was only seen following acute stress. Our findings revealed a strict interplay between RBFOX1 and BDNF/TRKB in stress resilience and suggest that RBFOX1 LoF predisposes to psychiatric diseases through HPA axis hyperactivation during development, impairing adaptation and heightening vulnerability to allostatic overload.