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.

成纤维细胞生长因子 2 (FGF2) 参与情感行为的调节，并通过 Akt 和细胞外信号调节激酶 (ERK) 1/2 通路发挥抗抑郁作用。 Nudix 水解酶 6 (NUDT6) 蛋白由 FGF2 基因的反义链编码，其在情感行为调节中的作用尚不清楚。在这里，我们在海马中过度表达 NUDT6，并研究了其行为效应以及影响行为的潜在分子机制。我们发现，增加海马 NUDT6 会导致大鼠出现抑郁样行为，而不会改变 FGF2 水平或激活其下游效应器 Akt 和 ERK1/2。相反，NUDT6 通过诱导炎症信号传导起作用，特别是通过增加 S100 钙结合蛋白 A9 (S100A9) 水平、激活核因子 kappa B-p65 (NF-κB-p65) 以及增加小胶质细胞数量并减少神经发生。我们的结果表明，NUDT6 可能通过诱导促炎症状态在重度抑郁症中发挥作用。这是反义蛋白通过与有义蛋白调节不同的作用机制发挥作用的第一份报告。 NUDT6 和 FGF2 对抑郁样行为的相反作用可能作为微调情感行为的机制。我们的研究结果为研究神经功能和行为以及神经精神疾病中正义和反义蛋白的差异调节和功能相互作用开辟了新的场所。