Growth differentiation factor-15 promotes glutamate release in medial prefrontal cortex of mice through upregulation of T-type calcium channels.
Growth differentiation factor-15 promotes glutamate release in medial prefrontal cortex of mice through upregulation of T-type calcium channels.
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生长分化因子-15通过上调T型钙通道促进小鼠内侧前额叶皮层谷氨酸释放
DOI：
10.1038/srep28653
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发表时间：
2016-06-29
影响因子：
4.6
通讯作者：
Mei YA
中科院分区：
文献类型：
--
作者：
Liu DD;Lu JM;Zhao QR;Hu C;Mei YA
生长分化因子 15 (GDF-15) 与缺血性脑损伤和突触发育有关，但其在调节神经元兴奋性和突触传递中的作用仍知之甚少。在这项研究中，我们研究了 GDF-15 对小鼠非诱发性微型兴奋性突触后电流 (mEPSC) 和内侧前额叶皮层 (mPFC) 神经递质释放的影响。 mPFC 切片与 GDF-15 一起孵育 60 分钟显着增加了 mEPSC 的频率，但对其振幅没有影响。 HPLC 表明，GDF-15 还显着提高了突触前谷氨酸的释放。这些作用可被 TGF-β I 型受体 (TβRI) 和 TGF-β II 型受体 (TβRII) 双重拮抗剂阻断，但不能被单独的 TβRI 拮抗剂阻断。同时，GDF-15 增强了 pERK 水平，而 MAPK/ERK 活性的抑制则减弱了 GDF-15 诱导的 mEPSC 和谷氨酸释放的增加。阻断 T 型钙通道可减少 GDF-15 诱导的突触传递上调。膜蛋白提取和细胞内蛋白转运抑制剂的使用表明，GDF-15 通过转运到膜来促进 CaV3.1 和 CaV3.3 α 亚基的表达。这些结果证实了之前在小脑颗粒神经元中的发现，其中 GDF-15 通过 TβRII 和 ERK 通路的激活诱导其神经生物学效应，为 GDF-15 在皮质神经元中的功能机制提供了新的见解。
Growth differentiation factor-15 (GDF-15) has been implicated in ischemic brain injury and synapse development, but its involvement in modulating neuronal excitability and synaptic transmission remain poorly understood. In this study, we investigated the effects of GDF-15 on non-evoked miniature excitatory post-synaptic currents (mEPSCs) and neurotransmitter release in the medial prefrontal cortex (mPFC) in mice. Incubation of mPFC slices with GDF-15 for 60 min significantly increased the frequency of mEPSCs without effect on their amplitude. GDF-15 also significantly elevated presynaptic glutamate release, as shown by HPLC. These effects were blocked by dual TGF-β type I receptor (TβRI) and TGF-β type II receptor (TβRII) antagonists, but not by a TβRI antagonist alone. Meanwhile, GDF-15 enhanced pERK level, and inhibition of MAPK/ERK activity attenuated the GDF-15-induced increases in mEPSC and glutamate release. Blocking T-type calcium channels reduced the GDF-15 induced up-regulation of synaptic transmission. Membrane-protein extraction and use of an intracellular protein-transport inhibitor showed that GDF-15 promoted CaV3.1 and CaV3.3 α-subunit expression by trafficking to the membrane. These results confirm previous findings in cerebellar granule neurons, in which GDF-15 induces its neurobiological effects via TβRII and activation of the ERK pathway, providing novel insights into the mechanism of GDF-15 function in cortical neurons.