Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
Cell Rep. 2013 Aug 29;4(4):724-37. doi: 10.1016/j.celrep.2013.07.028. Epub 2013 Aug 22.
Peroxisome proliferator-activated receptor α (PPARα) is a transcription factor that regulates genes involved in fatty acid catabolism. Here, we provide evidence that PPARα is constitutively expressed in nuclei of hippocampal neurons and, surprisingly, controls calcium influx and the expression of various plasticity-related genes via direct transcriptional regulation of cyclic AMP response element binding (CREB). Accordingly, Pparα-null, but not Pparβ-null, mice are deficient in CREB and memory-associated proteins and have decreased spatial learning and memory. Small hairpin RNA knockdown of PPARα in the hippocampus suppressed CREB and NR2A, rendering wild-type animals markedly poor in consolidating spatial memory, whereas introduction of PPARα to the hippocampus of Pparα-null mice increased hippocampal CREB and NR2A and improved spatial learning and memory. Through detailed analyses of CREB and NR2A activity, as well as spatial learning and memory in bone marrow chimeric animals lacking PPARα in the CNS, we uncover a mechanism for transcriptional control of Creb and associated plasticity genes by PPARα.
过氧化物酶体增殖物激活受体α（PPARα）是一种转录因子，可调节脂肪酸代谢相关基因的表达。本文提供的证据表明，PPARα在海马神经元核中持续表达，令人惊讶的是，它通过对环腺苷酸反应元件结合蛋白（CREB）的直接转录调控，控制钙内流和各种与可塑性相关基因的表达。因此，Pparα 基因敲除而不是 Pparβ 基因敲除的小鼠 CREB 和与记忆相关的蛋白表达减少，空间学习和记忆能力降低。海马体中 PPARα 的短发夹 RNA 敲低抑制了 CREB 和 NR2A，使野生型动物在巩固空间记忆方面明显较差，而将 PPARα 导入 Pparα 基因敲除小鼠的海马体中则增加了海马体中的 CREB 和 NR2A，并改善了空间学习和记忆。通过对中枢神经系统缺乏 PPARα 的骨髓嵌合动物中 CREB 和 NR2A 的活性以及空间学习和记忆的详细分析，我们揭示了 PPARα 对 Creb 和相关可塑性基因的转录调控机制。
