期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：42
页码：E5744-E5752
DOI：10.1073/pnas.1510239112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceChronic reduction of synaptic activity in neural networks leads to compensatory changes at both excitatory and inhibitory synapses, a phenomenon known as homeostatic synaptic plasticity. Postsynaptic activity/Ca2+-dependent regulation of retinoic acid (RA) synthesis is critically involved in homeostatic synaptic plasticity; however, the signaling molecule that gates RA synthesis in response to Ca2+ level changes remains unknown. Using pharmacologic and genetic manipulations, we show that calcineurin (CaN) activity, which is regulated by postsynaptic Ca2+ levels, directly controls RA synthesis. Inhibiting CaN activity or genetic ablation of CaN leads to homeostatic modulation of synaptic transmission in an RA signaling-dependent manner. These findings uncover the molecular mechanism by which activity regulates synaptic strength through RA synthesis. Homeostatic synaptic plasticity is a form of non-Hebbian plasticity that maintains stability of the network and fidelity for information processing in response to prolonged perturbation of network and synaptic activity. Prolonged blockade of synaptic activity decreases resting Ca2+ levels in neurons, thereby inducing retinoic acid (RA) synthesis and RA-dependent homeostatic synaptic plasticity; however, the signal transduction pathway that links reduced Ca2+-levels to RA synthesis remains unknown. Here we identify the Ca2+-dependent protein phosphatase calcineurin (CaN) as a key regulator for RA synthesis and homeostatic synaptic plasticity. Prolonged inhibition of CaN activity promotes RA synthesis in neurons, and leads to increased excitatory and decreased inhibitory synaptic transmission. These effects of CaN inhibitors on synaptic transmission are blocked by pharmacological inhibitors of RA synthesis or acute genetic deletion of the RA receptor RAR. Thus, CaN, acting upstream of RA, plays a critical role in gating RA signaling pathway in response to synaptic activity. Moreover, activity blockade-induced homeostatic synaptic plasticity is absent in CaN knockout neurons, demonstrating the essential role of CaN in RA-dependent homeostatic synaptic plasticity. Interestingly, in GluA1 S831A and S845A knockin mice, CaN inhibitor- and RA-induced regulation of synaptic transmission is intact, suggesting that phosphorylation of GluA1 C-terminal serine residues S831 and S845 is not required for CaN inhibitor- or RA-induced homeostatic synaptic plasticity. Thus, our study uncovers an unforeseen role of CaN in postsynaptic signaling, and defines CaN as the Ca2+-sensing signaling molecule that mediates RA-dependent homeostatic synaptic plasticity.
