NAD(P)⁺ transhydrogenase (NNT) links redox states of the mitochondrial NAD(H) and NADP(H) via a reaction coupled to proton-motive force across the inner mitochondrial membrane. NNT is believed to be ubiquitously present in mammalian cells, but its expression may vary substantially in different tissues. The present study investigated the tissue distribution and possible roles of NNT in the mouse brain. The pons exhibited high NNT expression/activity, and immunohistochemistry revealed intense NNT labeling in neurons from brainstem nuclei. In some of these regions, neuronal NNT labeling was strongly colocalized with enzymes involved in the biosynthesis of 5-hydroxytryptamine (5-HT) and nitric oxide (NO), which directly or indirectly require NADPH. Behavioral tests were performed in mice lacking NNT activity (Nnt^−/−, mice carrying the mutated Nnt^C57BL/6J allele from the C57BL/6J strain) and the Nnt^+/+ controls. Our data demonstrated that aged Nnt^−/− mice (18–20 months old), but not adult mice (3–4 months old), showed an increased immobility time in the tail suspension test that was reversed by fluoxetine treatment, providing evidence of depressive-like behavior in these mice. Aged Nnt^−/− mice also exhibited behavioral changes and impaired locomotor activity in the open field and rotarod tests. Despite the colocalization between NNT and NO synthase, the S-nitrosation and cGMP levels were independent of the Nnt genotype. Taken together, our results indicated that NNT is unevenly distributed throughout the brain and associated with 5-THergic and NOergic neurons. The lack of NNT led to alterations in brain functions related to mood and motor behavior/performance in aged mice.

NAD（P）⁺转氢酶（NNT）通过耦合到跨内线粒体膜的质子动力的反应，连接线粒体NAD（H）和NADP（H）的氧化还原状态。NNT被认为普遍存在于哺乳动物细胞中，但其表达在不同组织中可能存在很大差异。本研究调查了小鼠脑中NNT的组织分布和可能的作用。桥表现出高的NNT表达/活性，并且免疫组织化学显示脑干核神经元中强烈的NNT标记。在其中一些区域，神经元NNT标记与5-羟色胺（5-HT）和一氧化氮（否），直接或间接需要NADPH。在缺乏NNT活性的小鼠（Nnt ^-/-，携带来自C57BL / 6J菌株的突变的Nnt ^{C57BL / 6J}等位基因的小鼠）和Nnt ^+/-小鼠中进行了行为测试。我们的数据表明，年龄较大的Nnt ^-/-小鼠（18–20个月大）而非成年小鼠（3–4个月大）在尾部悬吊测试中显示了更长的固定时间，而氟西汀治疗可以逆转固定时间，这提供了证据这些小鼠的抑郁样行为。老年Nnt ^-/-小鼠在野外和旋转试验中也表现出行为改变和运动活动受损。尽管NNT和NO合酶，S亚硝化和cGMP水平与Nnt基因型无关。两者合计，我们的结果表明NNT在整个大脑中分布不均，并且与5-THergic和NOergic神经元有关。NNT的缺乏导致了与老年小鼠的情绪和运动行为/表现有关的脑功能改变。