FGF2 gene's antisense protein, NUDT6, plays a depressogenic role by promoting inflammation and suppressing neurogenesis without altering FGF2 signalling

Fibroblast growth factor‐2 (FGF2) is involved in the regulation of affective behaviour and shows antidepressant effects through the Akt and extracellular signal regulated kinase (ERK) 1/2 pathways. Nudix hydrolase 6 (NUDT6) protein is encoded from FGF2 gene's antisense strand and its role in the regulation of affective behaviour is unknown. Here, we overexpressed NUDT6 in the hippocampus and investigated its behavioural effects and the underlying molecular mechanisms affecting the behaviour. We showed that increasing hippocampal NUDT6 results in depression‐like behaviour in rats without changing FGF2 levels or activating its downstream effectors, Akt and ERK1/2. Instead, NUDT6 acted by inducing inflammatory signalling, specifically by increasing S100 calcium binding protein A9 (S100A9) levels, activating nuclear factor‐kappa B‐p65 (NF‐κB‐p65), and elevating microglia numbers along with a reduction in neurogenesis. Our results suggest that NUDT6 could play a role in major depression by inducing a proinflammatory state. This is the first report of an antisense protein acting through a different mechanism of action than regulation of its sense protein. The opposite effects of NUDT6 and FGF2 on depression‐like behaviour may serve as a mechanism to fine‐tune affective behaviour. Our findings open up new venues for studying the differential regulation and functional interactions of sense and antisense proteins in neural function and behaviour, as well as in neuropsychiatric disorders. Key points Hippocampal overexpression of nudix hydrolase 6 (NUDT6), the antisense protein of fibroblast growth factor‐2 (FGF2), increases depression‐like behaviour in rats. Hippocampal NUDT6 overexpression triggers a neuroinflammatory cascade by increasing S100 calcium binding proteinA9 (S100A9) expression and nuclear NF‐κB‐p65 translocation in neurons, in addition to microglial recruitment and activation. Hippocampal NUDT6 overexpression suppresses neurogenesis. NUDT6 exerts its actions without altering the levels or downstream signalling pathways of FGF2. figure legend Hippocampal overexpression of nudix hydrolase 6 (NUDT6), the antisense protein of fibroblast growth factor‐2, increases depression‐like behaviour in rats by triggering a neuroinflammatory cascade through increased S100 calcium binding protein A9 (S100A9) expression and nuclear NF‐κB‐p65 translocation in neurons accompanied by suppressed neurogenesis, in addition to microglial recruitment and activation.