Laboratory of Molecular Signaling, Division of Intramural Clinical and Biological Research, National Institutes on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Bethesda, MD 20892-9410, USA.
Biochem J. 2011 Apr 15;435(2):327-36. doi: 10.1042/BJ20102118.
DHA (docosahexaenoic acid, C22:6,n-3) has been shown to promote neurite growth and synaptogenesis in embryonic hippocampal neurons, supporting the importance of DHA known for hippocampus-related learning and memory function. In the present study, we demonstrate that DHA metabolism to DEA (N-docosahexaenoylethanolamide) is a significant mechanism for hippocampal neuronal development, contributing to synaptic function. We found that a fatty acid amide hydrolase inhibitor URB597 potentiates DHA-induced neurite growth, synaptogenesis and synaptic protein expression. Active metabolism of DHA to DEA was observed in embryonic day 18 hippocampal neuronal cultures, which was increased further by URB597. Synthetic DEA promoted hippocampal neurite growth and synaptogenesis at substantially lower concentrations in comparison with DHA. DEA-treated neurons increased the expression of synapsins and glutamate receptor subunits and exhibited enhanced glutamatergic synaptic activity, as was the case for DHA. The DEA level in mouse fetal hippocampi was altered according to the maternal dietary supply of n-3 fatty acids, suggesting that DEA formation is a relevant in vivo process responding to the DHA status. In conclusion, DHA metabolism to DEA is a significant biochemical mechanism for neurite growth, synaptogenesis and synaptic protein expression, leading to enhanced glutamatergic synaptic function. The novel DEA-dependent mechanism offers a new molecular insight into hippocampal neurodevelopment and function.
二十二碳六烯酸（DHA，C22:6，n-3）已被证明可促进胚胎海马神经元的轴突生长和突触形成，这支持了 DHA 对海马体相关学习和记忆功能的重要性。在本研究中，我们证明了 DHA 代谢为二高-γ-亚麻酸（DEA，N-二十二碳六烯酰乙醇胺）是海马神经元发育的重要机制，有助于突触功能。我们发现脂肪酸酰胺水解酶抑制剂 URB597 可增强 DHA 诱导的轴突生长、突触形成和突触蛋白表达。在胚胎第 18 天的海马神经元培养物中观察到 DHA 向 DEA 的主动代谢，URB597 进一步增加了这种代谢。与 DHA 相比，合成的 DEA 以低得多的浓度促进海马神经元的轴突生长和突触形成。用 DEA 处理的神经元增加了突触蛋白和谷氨酸受体亚基的表达，并表现出增强的谷氨酸能突触活性，这与 DHA 的情况相同。根据母体膳食中 n-3 脂肪酸的供应，改变了小鼠胎鼠海马中的 DEA 水平，这表明 DEA 的形成是一种与 DHA 状态相关的体内相关过程。总之，DHA 代谢为 DEA 是轴突生长、突触形成和突触蛋白表达的重要生化机制，导致增强的谷氨酸能突触功能。新的 DEA 依赖性机制为海马体神经发育和功能提供了新的分子见解。
