Structure of Excitatory Synapses and GABAA Receptor Localization at Inhibitory Synapses Are Regulated by Neuroplastin-65
Structure of Excitatory Synapses and GABAA Receptor Localization at Inhibitory Synapses Are Regulated by Neuroplastin-65
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DOI：
10.1074/jbc.m113.514992
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发表时间：
2014-03-28
影响因子：
4.8
通讯作者：
Montag, Dirk
中科院分区：
文献类型：
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作者：
Herrera-Molina, Rodrigo;Sarto-Jackson, Isabella;Montag, Dirk
背景：突触兴奋与抑制的比率对于大脑功能至关重要，但对其调节机制知之甚少。结果：细胞粘附分子 Neuroplastin-65 调节兴奋性突触的接触和稳定性以及 GABA(A)R 2 亚基在抑制性突触的定位。结论：Neuroplastin-65 介导特定的神经元连接并调节海马神经元突触的数量和功能。意义：特定大脑区域的正确神经元网络活动可能取决于 Neuroplastin-65。兴奋性和抑制性突触的形成、维持和活动对于神经元网络功能至关重要。细胞粘附分子（CAM）在这些过程中发挥着至关重要的作用。 CAM 神经塑蛋白 65 (Np65) 在突触形成和稳定期间高度表达，存在于突触前膜和突触后膜上。 Np65 可以响应电刺激而易位到突触中，并与抑制性突触中的 GABA(A) 受体亚型相互作用。在此，我们报道在小鼠海马和海马原代培养物中，CA1 区和齿状回 (DG) 的神经元表达高水平的 Np65，而 CA3 神经元的表达水平较低。在神经塑蛋白缺陷 (Np-/-) 小鼠中，CA1 和 DG 区域的兴奋性突触数量减少，但 CA3 区域的兴奋性突触数量没有减少。值得注意的是，该图在成熟的 Np-/- 海马培养物或用功能阻断性重组 Np65-Fc 胞外片段处理的成熟 CA1 和 DG 野生型 (Np+/+) 神经元中得到了反映。尽管 Np-/- 神经元或成熟 Np65-Fc 处理的 Np+/+ 神经元中 GABA 能突触的数量没有变化，但 Np-/- 培养物中兴奋性突触与抑制性突触的比率显着较低。此外，随着 1:2 GABA(A) 受体亚基比例的增加，Np-/- 神经元抑制性突触的 GABA(A) 受体组成发生改变。通过评估突触前释放功能并使用膜片钳记录，证实了 Np-/- 神经元兴奋性和抑制性突触功能的变化。这些数据表明，Np65 是海马突触数量和功能的重要调节因子。
Background: Synaptic excitatory to inhibitory ratio is crucial for brain function but its regulation is poorly understood. Results: The cell adhesion molecule neuroplastin-65 regulates contact and stability of excitatory synapses and localization of GABA(A)R 2 subunits at inhibitory synapses. Conclusion: Neuroplastin-65 mediates specific neuronal connections and regulates the number and function of synapses in hippocampal neurons. Significance: Correct neuronal network activity in specific brain regions may depend on neuroplastin-65.Formation, maintenance, and activity of excitatory and inhibitory synapses are essential for neuronal network function. Cell adhesion molecules (CAMs) are crucially involved in these processes. The CAM neuroplastin-65 (Np65) highly expressed during periods of synapse formation and stabilization is present at the pre- and postsynaptic membranes. Np65 can translocate into synapses in response to electrical stimulation and it interacts with subtypes of GABA(A) receptors in inhibitory synapses. Here, we report that in the murine hippocampus and in hippocampal primary culture, neurons of the CA1 region and the dentate gyrus (DG) express high Np65 levels, whereas expression in CA3 neurons is lower. In neuroplastin-deficient (Np-/-) mice the number of excitatory synapses in CA1 and DG, but not CA3 regions is reduced. Notably this picture is mirrored in mature Np-/- hippocampal cultures or in mature CA1 and DG wild-type (Np+/+) neurons treated with a function-blocking recombinant Np65-Fc extracellular fragment. Although the number of GABAergic synapses was unchanged in Np-/- neurons or in mature Np65-Fc-treated Np+/+ neurons, the ratio of excitatory to inhibitory synapses was significantly lower in Np-/- cultures. Furthermore, GABA(A) receptor composition was altered at inhibitory synapses in Np-/- neurons as the 1 to 2 GABA(A) receptor subunit ratio was increased. Changes of excitatory and inhibitory synaptic function in Np-/- neurons were confirmed evaluating the presynaptic release function and using patch clamp recording. These data demonstrate that Np65 is an important regulator of the number and function of synapses in the hippocampus.