TY - JOUR
T1 - Accelerated Experience-Dependent Pruning of Cortical Synapses in Ephrin-A2 Knockout Mice
AU - Yu, Xinzhu
AU - Wang, Gordon
AU - Gilmore, Anthony
AU - Yee, Ada Xin
AU - Li, Xiang
AU - Xu, Tonghui
AU - Smith, Stephen J.
AU - Chen, Lu
AU - Zuo, Yi
N1 - Funding Information:
We gratefully thank David Feldheim for providing ephrin-A2 and ephrin-A3 KO mice; Jeffrey Rothstein for providing GLAST and GLT-1 antibodies; Yi Qin, Ju Lu, and David States for critical comments on the manuscript; Shinya Ito for help with spine lifetime analysis; and Shibo Li, Zhuojun Guo, Maria Ximena Silveyra, Michael Robinson, Benjamin Abrams, Adam Aharon, James Perna, Rebecca Roberts, Andrew Perlik, and Jonathan Zweig for suggestions and assistance with experiments. This work was supported by grants from the National Institute of Mental Health to Y.Z. S.J.S. is a founder of Aratome and chair of its scientific advisory board.
Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 2013/10/2
Y1 - 2013/10/2
N2 - Refinement of mammalian neural circuits involves substantial experience-dependent synapse elimination. Using invivo two-photon imaging, we found that experience-dependent elimination of postsynaptic dendritic spines in the cortex was accelerated in ephrin-A2 knockout (KO) mice, resulting in fewer adolescent spines integrated into adult circuits. Such increased spine removal in ephrin-A2 KOs depended on activation of glutamate receptors, as blockade of the N-methyl-D-aspartate (NMDA) receptors eliminated the difference in spine loss between wild-type and KO mice. We also showed that ephrin-A2 in the cortex colocalized with glial glutamate transporters, which were significantly downregulated in ephrin-A2 KOs. Consistently, glial glutamate transport was reduced in ephrin-A2 KOs, resulting in an accumulation of synaptic glutamate. Finally, inhibition of glial glutamate uptake promoted spine elimination in wild-type mice, resembling the phenotype of ephrin-A2 KOs. Together, our results suggest that ephrin-A2 regulates experience-dependent, NMDA receptor-mediated synaptic pruning through glial glutamate transport during maturation of the mouse cortex
AB - Refinement of mammalian neural circuits involves substantial experience-dependent synapse elimination. Using invivo two-photon imaging, we found that experience-dependent elimination of postsynaptic dendritic spines in the cortex was accelerated in ephrin-A2 knockout (KO) mice, resulting in fewer adolescent spines integrated into adult circuits. Such increased spine removal in ephrin-A2 KOs depended on activation of glutamate receptors, as blockade of the N-methyl-D-aspartate (NMDA) receptors eliminated the difference in spine loss between wild-type and KO mice. We also showed that ephrin-A2 in the cortex colocalized with glial glutamate transporters, which were significantly downregulated in ephrin-A2 KOs. Consistently, glial glutamate transport was reduced in ephrin-A2 KOs, resulting in an accumulation of synaptic glutamate. Finally, inhibition of glial glutamate uptake promoted spine elimination in wild-type mice, resembling the phenotype of ephrin-A2 KOs. Together, our results suggest that ephrin-A2 regulates experience-dependent, NMDA receptor-mediated synaptic pruning through glial glutamate transport during maturation of the mouse cortex
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U2 - 10.1016/j.neuron.2013.07.014
DO - 10.1016/j.neuron.2013.07.014
M3 - Article
C2 - 24094103
AN - SCOPUS:84884754134
VL - 80
SP - 64
EP - 71
JO - Neuron
JF - Neuron
SN - 0896-6273
IS - 1
ER -