Editors' ChoiceNeuroscience

Scaling It Up with Retinoic Acid

Science Signaling  28 Oct 2008:
Vol. 1, Issue 43, pp. ec369
DOI: 10.1126/scisignal.143ec369

Synaptic scaling is a homeostatic mechanism in which the overall strength of synapses onto a neuron adjusts in response to long-term changes in activity (see Groth and Tsien). For example, central neurons in which activity is inhibited with a combination of the sodium channel blocker tetrodotoxin (TTX) and the N-methyl-D-aspartate (NMDA)-type glutamate receptor antagonist APV (TTX + APV) show a compensatory increase in the number of postsynaptic AMPA-type glutamate receptors and the amplitude of spontaneous miniature excitatory postsynaptic currents (mEPSCs). Aoto et al. found that exposure to the vitamin A derivative all-trans retinoic acid (RA) stimulated an increase in the amplitude of mEPSCs on hippocampal pyramidal neurons in slices and dissociated cultures. Inhibition of RA synthesis blocked the TTX + APV–dependent increase in mEPSC amplitude, whereas prior induction of synaptic scaling by TTX + APV abrogated the effects of RA. Moreover, TTX + APV stimulated the transcription of a transfected retinoic acid response element–containing reporter. Treatment with RA or TTX + APV increased the surface abundance of GluR1 AMPA receptor subunits; however, the combination of RA and TTX + APV failed to produce a greater increase than either alone. Noting that TTX + APV elicit synaptic scaling through dendritic protein translation, the authors determined that the increase in surface GluR1 and mEPSC amplitude was blocked by protein synthesis inhibitors but not by inhibiting transcription, as was an RA-mediated increase in GluR1 in synaptoneurosomes (a preparation enriched in synaptic proteins and lacking nuclei). Intriguingly, the α isotype of the retinoic acid receptor (RARα, a nuclear receptor) was present in synaptoneurosomes and in the dendrites of hippocampal pyramidal cells. Furthermore, RARα knockdown in cultured neurons blocked the TTX + APV–dependent increase in mEPSC amplitude and surface GluR1 abundance without affecting basal synaptic transmission, spine density, or GluR1 expression. The authors conclude that RA increases synaptic strength in a homeostatic response to inactivity through a mechanism involving protein synthesis.

R. D. Groth, R. W. Tsien, A role for retinoic acid in homeostatic plasticity. Neuron 60, 192-194 (2008). [Online Journal]

J. Aoto, C. I. Nam, M. M. Poon, P. Ting, L. Chen, Synaptic signaling by all-trans retinoic acid in homeostatic synaptic plasticity. Neuron 60, 308-320 (2008). [Online Journal]