Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors.
Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors.
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DOI：
10.1038/nature11059
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发表时间：
2012-05-27
期刊：
影响因子：
64.8
通讯作者：
Barres, Ben A.
中科院分区：
文献类型：
--
作者：
Allen, Nicola J.;Bennett, Mariko L.;Foo, Lynette C.;Wang, Gordon X.;Chakraborty, Chandrani;Smith, Stephen J.;Barres, Ben A.
在发育中的中枢神经系统（CNS）中，突触数量和功能的控制对于神经回路的形成至关重要。我们以前证明，星形胶质细胞分泌的因子强烈诱导中枢神经系统神经元之间的功能性兴奋性突触的形成。星形胶质细胞分泌的血小板反应蛋白诱导结构性突触，然而这些突触是突触后沉默的。在这里，我们使用生化分离的星形胶质细胞条件培养基（ACM），以确定磷脂酰肌醇蛋白聚糖4（Gpc4）和6（Gpc6）作为星形胶质细胞分泌的信号足以诱导纯化的视网膜神经节细胞（RGC）神经元之间的功能性突触，并显示这些分子从ACM的耗尽显着降低其诱导突触后活动的能力。将Gpc 4应用于纯化的神经元足以增加突触能突触事件的频率和振幅。这是通过增加AMPA谷氨酸受体（AMPAR）的GluA1亚基的表面水平和聚集而不是整体细胞蛋白水平来实现的。Gpc 4和6在发育中的CNS中由体内星形胶质细胞表达，其中Gpc 4表达在海马中富集，Gpc 6在小脑中富集。最后，我们证明，Gpc4缺陷的小鼠有缺陷的突触形成，在发育中的海马和减少招募的AMPAR突触兴奋性突触电流的幅度降低。这些数据确定磷脂酰肌醇蛋白聚糖作为一个家庭的新的星形胶质细胞衍生的分子，是必要的和足够的，以促进谷氨酸受体聚集和接受性，并诱导形成突触后功能的中枢神经系统突触。
In the developing central nervous system (CNS), the control of synapse number and function is critical to the formation of neural circuits. We previously demonstrated that astrocyte-secreted factors powerfully induce the formation of functional excitatory synapses between CNS neurons. Astrocyte-secreted thrombospondins induce structural synapses, however these synapses are post-synaptically silent. Here we use biochemical fractionation of astrocyte conditioned media (ACM) to identify glypican 4 (Gpc4) and 6 (Gpc6) as astrocyte-secreted signals sufficient to induce functional synapses between purified retinal ganglion cell (RGC) neurons, and show that depletion of these molecules from ACM significantly reduces its ability to induce postsynaptic activity. Application of Gpc4 to purified neurons is sufficient to increase the frequency and amplitude of glutamatergic synaptic events. This is achieved by increasing the surface level and clustering, but not overall cellular protein level, of the GluA1 subunit of the AMPA glutamate receptor (AMPAR). Gpc4&6 are expressed by astrocytes in vivo in the developing CNS, with Gpc4 expression enriched in the hippocampus and Gpc6 in the cerebellum. Finally, we demonstrate that Gpc4-deficient mice have defective synapse formation, with decreased amplitude of excitatory synaptic currents in the developing hippocampus and reduced recruitment of AMPARs to synapses. These data identify glypicans as a family of novel astrocyte-derived molecules that are necessary and sufficient to promote glutamate receptor clustering and receptivity and induce the formation of post-synaptically functioning CNS synapses.
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影响因子：
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