Synaptic signaling by all-trans retinoic acid in homeostatic synaptic plasticity

Neuron. 2008 Oct 23;60(2):308-20. doi: 10.1016/j.neuron.2008.08.012.


Normal brain function requires that the overall synaptic activity in neural circuits be kept constant. Long-term alterations of neural activity lead to homeostatic regulation of synaptic strength by a process known as synaptic scaling. The molecular mechanisms underlying synaptic scaling are largely unknown. Here, we report that all-trans retinoic acid (RA), a well-known developmental morphogen, unexpectedly mediates synaptic scaling in response to activity blockade. We show that activity blockade increases RA synthesis in neurons and that acute RA treatment enhances synaptic transmission. The RA-induced increase in synaptic strength is occluded by activity blockade-induced synaptic scaling. Suppression of RA synthesis prevents synaptic scaling. This form of RA signaling operates via a translation-dependent but transcription-independent mechanism, causes an upregulation of postsynaptic glutamate receptor levels, and requires RARalpha receptors. Together, our data suggest that RA functions in homeostatic plasticity as a signaling molecule that increases synaptic strength by a protein synthesis-dependent mechanism.

Publication types

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

MeSH terms

  • Animals
  • Cells, Cultured
  • Hippocampus / cytology
  • Hippocampus / metabolism*
  • Homeostasis / drug effects
  • Homeostasis / physiology
  • Immunohistochemistry
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology*
  • Organ Culture Techniques
  • Patch-Clamp Techniques
  • Protein Biosynthesis / genetics
  • Pyramidal Cells / cytology
  • Pyramidal Cells / drug effects
  • Pyramidal Cells / metabolism*
  • RNA, Small Interfering / genetics
  • Rats
  • Receptors, AMPA / biosynthesis*
  • Receptors, AMPA / genetics
  • Receptors, Retinoic Acid / genetics
  • Receptors, Retinoic Acid / metabolism
  • Retinoic Acid Receptor alpha
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology*
  • Transfection
  • Tretinoin / metabolism*
  • Tretinoin / pharmacology
  • Up-Regulation / drug effects
  • Up-Regulation / physiology


  • RNA, Small Interfering
  • Rara protein, rat
  • Receptors, AMPA
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • Tretinoin
  • glutamate receptor ionotropic, AMPA 1