Department of Molecular Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
Neuron. 2013 Oct 2;80(1):64-71. doi: 10.1016/j.neuron.2013.07.014.
Refinement of mammalian neural circuits involves substantial experience-dependent synapse elimination. Using in vivo 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.
哺乳动物神经回路的精细化涉及大量依赖经验的突触消除。通过在体双光子成像，我们发现，在 Ephrin-A2 敲除（KO）小鼠中，皮质中依赖经验的突触后树突棘的消除速度加快，导致较少的青春期树突棘整合到成年回路中。Ephrin-A2 KO 中这种增加的棘突去除依赖于谷氨酸受体的激活，因为 NMDA 受体的阻断消除了野生型和 KO 小鼠之间棘突丢失的差异。我们还表明，皮质中的 Ephrin-A2 与神经胶质谷氨酸转运体共定位，而 Ephrin-A2 KO 中这些转运体明显下调。一致地，Ephrin-A2 KO 中神经胶质谷氨酸转运减少，导致突触谷氨酸积累。最后，抑制神经胶质谷氨酸摄取促进了野生型小鼠的棘突消除，类似于 Ephrin-A2 KO 的表型。总之，我们的结果表明，Ephrin-A2 通过成熟过程中神经胶质谷氨酸转运调节依赖经验的、NMDA 受体介导的突触修剪。
