BDNF对脊髓二级感觉投射神经元GABAA受体的调节机制及其在内脏痛中的作用

项目名称： BDNF对脊髓二级感觉投射神经元GABAA受体的调节机制及其在内脏痛中的作用

项目编号： No.81470910

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 马雪莲

作者单位： 山东大学

项目金额： 67万元

中文摘要： 内脏痛是功能性胃肠道疾病最常见的症状之一，但其发生机制还不清楚。我们研究发现直结肠扩张内脏痛模型中脊髓后角浅层BDNF表达增多、神经元细胞膜中GABA A受体蛋白水平升高，抑制内脏痛的发生，但其作用机制尚不清楚。进一步研究发现BDNF通过激活PI3K-Akt和PLCγ两条途径诱导GABA A受体膜蛋白水平升高。我们根据预实验结果推测在脊髓第二级感觉神经元中，BDNF一方面激活PLCγ-IP3-Ca2+/CaMKⅡ信号通路磷酸化GABA A受体，诱导其转运、上膜及功能改变；另一方面通过激活Akt，抑制GSK3-β对锚定蛋白gephyrin的磷酸化，增强GABA A受体在细胞膜上的稳定性。两条通路协同作用，抑制第二级感觉投射神经元的兴奋性，抑制内脏痛的发生。该课题拟应用膜片钳记录、逆行示踪、钙成像及多种分子生物学方法，揭示BDNF抑制内脏痛的脊髓机制，为内脏痛的治疗提供新的理论依据和新手段。

中文关键词： 内脏高敏感性；脑源性神经生长因子；脊髓后角；GABA；A；受体；gephyrin

英文摘要： The mechanisms of functional gastrointestinal diseases are sitll not clear. Our previously data shown BDNF protein was upregulated in the superficial layers of spinal dorsal horn after colorectal distention (CRD), and the GABAA redeptor expression increased correspondingly. Enhancement of brain-derived neurotrophic factor (BDNF) attenuated visceral hypersensitivity . But the underlying mechanisms are still not clear. Further studies showed that BDNF induced GABAA receptor expression through activating PI3K-AKT and PLCγ pathways. According our previous results, we suspect that BDNF avtivates AKT and then inhibits the kinase activity of GSK3-β, inhibits the phosphorylation of gephyrin, and enhances the membrane stability of GABAA receptor. BDNF can also induce GABA A receptor expression through activating the PLCγ-IP3-Ca2+/CaMKⅡpathway. BDNF inhibits the excitability of the second-order neurons in the spinal dorsal horn and attenuates viceral nociception through both pathways. Thus, In this study, we propose to use patch clamp, retrograde tracing, cassium imaging, and molecular techaniques to study the possible spinal mechanisums of changes of visceral hypersensitivity. This research may disclose a new mechanisum and therapic target of visceral pain.

英文关键词： visceral hypersensitivity;brain-derived neurotrophic factor;spinal dorsal horn;GABA A receptor;gephyrin