Regulation of Cyclic AMP Response Element Binding and Hippocampal Plasticity-Related Genes by Peroxisome Proliferator-Activated Receptor α

Peroxisome proliferator-activated receptor alpha (PPAR alpha) is a transcription factor that regulates genes involved in fatty acid catabolism. Here, we provide evidence that PPAR alpha 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, Ppar alpha-null, but not Ppar beta-null, mice are deficient in CREB and memory-associated proteins and have decreased spatial learning and memory. Small hairpin RNA knockdown of PPAR alpha in the hippocampus suppressed CREB and NR2A, rendering wild-type animals markedly poor in consolidating spatial memory, whereas introduction of PPAR alpha to the hippocampus of Ppar alpha-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 PPAR alpha in the CNS, we uncover a mechanism for transcriptional control of Creb and associated plasticity genes by PPAR alpha.