Arachidonic acid (AA), a polyunsaturated fatty acid, is involved in the modulation of neuronal excitability in the brain. Arachidonate lipoxygenase 3 (ALOXE3), a critical enzyme in the AA metabolic pathway, catalyzes the derivate of AA into hepoxilins. However, the expression pattern of ALOXE3 and its role in the brain has not been described until now. Here we showed that the levels of Aloxe3 mRNA and protein kept increasing since birth and reached the highest level at postnatal day 30 in the mouse hippocampus and temporal cortex. Histomorphological analyses indicated that ALOXE3 was enriched in adult hippocampus, somatosensory cortex and striatum. The distribution was restricted to the neurites of function-specific subregions, such as mossy fibre connecting hilus and CA3 neurons, termini of Schaffer collateral projections, and the layers III and IV of somatosensory cortex. The spatiotemporal expression pattern of ALOXE3 suggests its potential role in the modulation of neural excitability and seizure susceptibility. In fact, decreased expression of ALOXE3 and elevated concentration of AA in the hippocampus was found after status epilepticus (SE) induced by pilocarpine. Local overexpression of ALOXE3 via adeno-associated virus gene transfer restored the elevated AA level induced by SE, alleviated seizure severities by increasing the latencies to myclonic switch, clonic convulsions and tonic hindlimb extensions, and decreased the mortality rate in the pilocarpine-induced SE model. These results suggest that the expression of ALOXE3 is a crucial regulator of AA metabolism in brain, and potentially acts as a regulator of neural excitability, thereby controlling brain development and seizure susceptibility.

花生四烯酸 (AA) 是一种多不饱和脂肪酸，参与调节大脑中的神经元兴奋性。花生四烯酸脂氧合酶 3 (ALOXE3) 是 AA 代谢途径中的一种关键酶，可催化 AA 衍生物生成 hepoxilins。然而，直到现在还没有描述 ALOXE3 的表达模式及其在大脑中的作用。在这里，我们展示了Aloxe3的水平mRNA和蛋白质自出生以来不断增加，并在小鼠海马和颞叶皮层的出生后第30天达到最高水平。组织形态学分析表明，ALOXE3 在成人海马、体感皮层和纹状体中富集。分布仅限于功能特异性亚区的神经突，如连接门和CA3神经元的苔藓纤维、Schaffer侧枝投射的末端以及体感皮层的III层和IV层。ALOXE3 的时空表达模式表明其在调节神经兴奋性和癫痫发作易感性中的潜在作用。事实上，在毛果芸香碱诱导的癫痫持续状态（SE）后，发现海马中 ALOXE3 的表达降低，AA 浓度升高。通过腺相关病毒基因转移局部过表达 ALOXE3 可恢复 SE 诱导的升高的 AA 水平，通过增加肌阵挛转换、阵挛性抽搐和强直性后肢伸展的潜伏期来减轻癫痫发作的严重程度，并降低毛果芸香碱诱导的 SE 模型的死亡率. 这些结果表明 ALOXE3 的表达是大脑中 AA 代谢的关键调节剂，并可能作为神经兴奋性的调节剂，从而控制大脑发育和癫痫易感性。