Regulation of cyclic AMP response element binding and hippocampal plasticity-related genes by peroxisome proliferator-activated receptor α

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Gene Expression Regulation*
  • Hippocampus / cytology
  • Hippocampus / metabolism*
  • Hippocampus / physiology
  • Macaca mulatta
  • Maze Learning
  • Memory
  • Mice
  • Mice, Inbred C57BL
  • Neurons / metabolism
  • PPAR alpha / genetics
  • PPAR alpha / metabolism*
  • Protein Binding
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Response Elements*
  • Synapses / metabolism
  • Synapses / physiology
  • Transcription, Genetic


  • Cyclic AMP Response Element-Binding Protein
  • NR2A NMDA receptor
  • PPAR alpha
  • Receptors, N-Methyl-D-Aspartate
  • Calcium