Astrocyte-Secreted Glypican 4 Regulates Release of Neuronal Pentraxin 1 from Axons to Induce Functional Synapse Formation.
Astrocyte-Secreted Glypican 4 Regulates Release of Neuronal Pentraxin 1 from Axons to Induce Functional Synapse Formation.
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DOI：
10.1016/j.neuron.2017.09.053
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发表时间：
2017-10-11
期刊：
影响因子：
16.2
通讯作者：
Allen NJ
中科院分区：
文献类型：
--
作者：
Farhy-Tselnicker I;van Casteren ACM;Lee A;Chang VT;Aricescu AR;Allen NJ
发育中的神经元之间精确突触连接的产生对于功能性神经回路的形成至关重要。星形胶质细胞分泌的磷脂酰肌醇蛋白聚糖 4 通过将 AMPA 谷氨酸受体募集到突触后细胞表面来诱导活性兴奋性突触的形成。我们现在确定了磷脂酰肌醇蛋白聚糖 4 如何发挥其作用的分子机制。磷脂酰肌醇蛋白聚糖 4 通过突触前蛋白酪氨酸磷酸酶受体 δ 发出信号，诱导突触前末梢释放 AMPA 受体聚集因子神经元五聚蛋白 1。 Pentraxin 然后在突触后末端积累 AMPA 受体，形成功能性突触。我们的研究结果揭示了在中枢神经系统发育过程中调节突触活动的信号通路，并证明星形胶质细胞通过协调突触前和突触后神经元作为活跃突触连接的组织者的作用。由于磷脂酰肌醇蛋白聚糖的突变与自闭症和精神分裂症等神经系统疾病有关，因此这种信号级联为调节疾病中的突触功能提供了新途径。星形胶质细胞分泌的 Gpc4 诱导神经元释放 NP1 NP1 的释放是通过 Gpc4 与突触前 RPTPδ 相互作用介导的 Gpc4 或 RPTPδ KO 导致突触前 NP1 保留和突触数量减少 星形胶质细胞释放 Gpc4 为突触发生提供空间和时间线索 星形胶质细胞是突触形成的重要调节因子。 Farhy-Tselnicker 等人。确定了星形胶质细胞分泌的磷脂酰肌醇蛋白聚糖 4 诱导的活跃神经元突触形成的分子途径。这些数据在功能上将星形胶质细胞与突触前和突触后神经元中激活的信号级联联系起来。
The generation of precise synaptic connections between developing neurons is critical to the formation of functional neural circuits. Astrocyte-secreted glypican 4 induces formation of active excitatory synapses by recruiting AMPA glutamate receptors to the postsynaptic cell surface. We now identify the molecular mechanism of how glypican 4 exerts its effect. Glypican 4 induces release of the AMPA receptor clustering factor neuronal pentraxin 1 from presynaptic terminals by signaling through presynaptic protein tyrosine phosphatase receptor δ. Pentraxin then accumulates AMPA receptors on the postsynaptic terminal forming functional synapses. Our findings reveal a signaling pathway that regulates synaptic activity during central nervous system development and demonstrates a role for astrocytes as organizers of active synaptic connections by coordinating both pre and post synaptic neurons. As mutations in glypicans are associated with neurological disorders, such as autism and schizophrenia, this signaling cascade offers new avenues to modulate synaptic function in disease. Astrocyte-secreted Gpc4 induces release of NP1 from neurons Release of NP1 is mediated through Gpc4 interaction with presynaptic RPTPδ Gpc4 or RPTPδ KO causes presynaptic NP1 retention and decreased synapse number Astrocytic release of Gpc4 provides spatial and temporal cues for synaptogenesis Astrocytes are important regulators of synapse formation. Farhy-Tselnicker et al. identify the molecular pathway of active neuronal synapse formation induced by astrocyte-secreted glypican 4. These data functionally link astrocytes to signaling cascades activated in both pre- and postsynaptic neurons.
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