Liu Dong-Dong, Lu Jun-Mei, Zhao Qian-Ru, Hu Changlong, Mei Yan-Ai
Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and School of Life Sciences, Fudan University, Shanghai 200433, China.
Sci Rep. 2016 Jun 29;6:28653. doi: 10.1038/srep28653.
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.
生长分化因子-15（GDF-15）已被证明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方面的作用仍知之甚少。在本研究中，我们调查了GDF-15对小鼠内侧前额叶皮质（mPFC）中未诱发的微小兴奋性突触后电流（mEPSCs）和神经递质释放的影响。用GDF-15孵育mPFC切片60分钟可显著增加mEPSCs的频率，但对其幅度没有影响。高效液相色谱法显示，GDF-15还显著提高了突触前谷氨酸的释放。这些作用被I型和II型转化生长因子β（TGF-β）受体双重拮抗剂阻断，但单独的I型TGF-β受体拮抗剂则不能。同时，GDF-15增强了磷酸化细胞外信号调节激酶（pERK）水平，抑制丝裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/ERK）活性可减弱GDF-15诱导的mEPSC增加和谷氨酸释放。阻断T型钙通道可降低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通过转运到膜上促进了CaV3.1和CaV3.3α亚基的表达。这些结果证实了先前在小脑颗粒神经元中的发现，即GDF-15通过TβRII和ERK途径的激活诱导其神经生物学效应，为GDF-15在皮质神经元中发挥功能的机制提供了新的见解。
