title: 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 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.
authors.affiliation: Stanford Institute of Neuro-Innovation and Translational Neuroscience and Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California 94305-5453, USA.
authors.forename: Hui-Li
authors.initials: HL
authors.lastname: Wang
authors.forename: Zhenjie
authors.initials: Z
authors.lastname: Zhang
authors.forename: Maik
authors.initials: M
authors.lastname: Hintze
authors.forename: Lu
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism; D004095:Dihydropyridines; D004622:Embryo, Mammalian; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D051381:Rats; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D004095:Dihydropyridines; D018691:Excitatory Amino Acid Antagonists; D026941:Sodium Channel Blockers; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D013779:Tetrodotoxin; D014212:Tretinoin; D002118:Calcium