Decrease in calcium concentration triggers neuronal retinoic acid synthesis during homeostatic synaptic plasticity.

Blockade of synaptic activity induces homeostatic plasticity, in part by stimulating synthesis of all-trans retinoic acid (RA), which in turn increases AMPA receptor synthesis. However, the synaptic signal that triggers RA synthesis remained unknown. Using multiple activity-blockade protocols that induce homeostatic synaptic plasticity, here we show that RA synthesis is activated whenever postsynaptic Ca(2+) entry is significantly decreased and that RA is required for upregulation of synaptic strength under these homeostatic plasticity conditions, suggesting that Ca(2+) plays an inhibitory role in RA synthesis. Consistent with this notion, we demonstrate that both transient Ca(2+) depletion by membrane-permeable Ca(2+) chelators and chronic blockage of L-type Ca(2+)-channels induces RA synthesis. Moreover, the source of dendritic Ca(2+) entry that regulates RA synthesis is not specific because mild depolarization with KCl is sufficient to reverse synaptic scaling induced by L-type Ca(2+)-channel blocker. By expression of a dihydropyridine-insensitive L-type Ca(2+) channel, we further show that RA acts cell autonomously to modulate synaptic transmission. Our findings suggest that, in synaptically active neurons, modest "basal" levels of postsynaptic Ca(2+) physiologically suppress RA synthesis, whereas in synaptically inactive neurons, decreases in the resting Ca(2+) levels induce homeostatic plasticity by stimulating synthesis of RA that then acts in a cell-autonomous manner to increase AMPA receptor function.