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

Abstract

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 up regulation 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. © 2011 the authors.