星形胶质细胞是大脑中数量最多的胶质细胞类型,在维持神经递质传递和血脑屏障的建立中发挥至关重要的作用。传统基于星形胶质细胞的位置和形态将其分为两大类,原浆星形胶质细胞和纤维星形胶质细胞[1]。另一种分类方法是基于抗原表型,在很大程度上依赖于最常见的胶质纤维酸性蛋白(glial fibrillary acidic protein,GFAP)、水通道蛋白4(aquaporin 4,AQP-4)、谷氨酸/天冬氨酸转运体(glutamate/aspartate transporter,GLAST)、谷氨酸转运体1(glutamate transporter 1,GLT-1)[2]。早期研究认为星形胶质细胞是被动的非兴奋支持细胞,为神经元提供支架,不参与突触传递,但后来研究发现星形胶质细胞表达大多数神经递质受体。更有研究表明星形胶质细胞比预期更为积极地参与突触传递过程[3]。星形胶质细胞调节突触传递的机制包括释放星形胶质源性神经活性物质以及响应神经兴奋所引起的神经递质流动的动态调节。此外,胶质细胞在受伤的大脑中存在特异反应。在神经病理条件下(包括急性脑损伤和神经退行性疾病),星形胶质细胞转变为激活状态,其功能也随之发生变化,从而进一步影响受损神经组织的修复[4]。这些结果表明星形胶质细胞能够在保护和修复损伤的神经组织中发挥有利作用。
抑郁症一直是精神障碍疾病中常见且棘手的问题,以持久的悲伤、压抑、内疚、自卑、睡眠不安、无食欲、疲劳感、注意力差,甚至想自杀为特点,20%的女性和15%的男性在其一生中至少有一个时期会遭受抑郁症的困扰[5]。在美国,抑郁症的患病率为16.2%[5]。据预测,到2030年,除心血管疾病外,抑郁症将成为人类健康的主要杀手[6]。有证据表明星形胶质细胞功能失调与抑郁症相关[7]。
1 星形胶质细胞释放的营养因子在抑郁症中的作用在正常情况下,星形胶质细胞释放多种营养因子和细胞因子,细胞激活后,对这些因子的分泌进一步增强[8],星形胶质细胞是脑病理条件下神经营养因子的主要来源[9]。营养因子是抑郁症发病机制的热门候选因子,已有科学家提出了抗抑郁作用的“神经营养假说” [10]。增加神经营养因子的产生可能会是抑郁症的一种有效治疗策略,因为其可以促进神经元和胶质细胞再生以及突触结构重塑。近来研究表明,胶质细胞源性神经营养因子(glial cell-derived neurotrophic factor,GDNF)除了是多巴胺能神经元的保护剂外,还有促进发育、分化以及保护中枢神经系统中其他神经元的作用,并且在各种精神疾病中扮演重要角色[11]。Meta分析研究表明抑郁症患者脑中GDNF表达水平下降[12]。研究表明GDNF[13]、脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)[14]和碱性成纤维细胞生长因子(basic fibroblast growth factor,bFGF)[15]水平在抑郁症患者大脑中的减少与海马神经再生减少有关。注射抗抑郁药物能够增加大鼠海马BDNF和GDNF的产生[16-17]。此外,抗抑郁药物处理星形胶质细胞后,可以增加其表达GDNF[18-19]等生长因子。BDNF前体与成熟的BDNF有着不同的生物学功能,组织型纤溶酶原激活剂(tissue-type plasminogen activator,tPA)对于BDNF前体裂解成为成熟BDNF至关重要。最新研究表明,抑郁症患者血清中的tPA和BDNF水平显著低于正常对照组,而BDNF前体水平高于正常对照组;给予患者艾司西酞普兰或度洛西汀治疗8周后可逆转这一情况,提示tPA-BDNF裂解途径可能与重度抑郁的发病机制密切相关,也可能是抗抑郁药发挥治疗作用的潜在机制[20]。另一研究发现,BDNF基因启动子甲基化水平的升高可能与重度抑郁症患者皮质变薄密切相关[21]。阿米替林、地昔帕明和氟西汀可诱导FGF受体信号级联的激活和大脑皮质、海马FGF2的表达。成纤维细胞生长因子是一种重要的生长因子,对突触的形成和成熟至关重要。因此,上调星形胶质细胞营养因子的产生可能是目前使用的抗抑郁药物产生治疗效果的原因之一。
2 星形胶质特异性蛋白分子在抑郁症中的作用抑郁症患者脑中星形胶质细胞的形态和功能发生了明显的改变[22],抑郁症患者死后的大脑检查显示海马[23]、蓝斑[24]、额叶皮质[25]以及杏仁核[26]中星形胶质细胞的数量和GFAP表达均下降。这些形态和功能上的变化可能是抑郁症的发病原因,也可能是抑郁症的病理生理结果。由于尸检研究的对象通常为各种抗抑郁药和(或)抗精神病药物治疗史的患者,因此,患者大脑中星形胶质细胞的变化也有可能是使用抗抑郁药物所导致的。一项非人类灵长类动物的研究表明,猕猴顶叶皮质下星形胶质细胞及少突胶质细胞数量的降低与动物长期暴露于抗精神病药物(氟哌啶醇与奥氮平)有关[27-28]。在慢性不可预见性动物模型(一种抑郁动物模型)中也发现星形胶质细胞数量和GFAP表达下降[29]。前额叶皮质注射L-α-氨基乙二酸(L-α-aminoadipate,可用来诱导特异的星形胶质细胞变性)会导致大鼠产生抑郁样行为[30]。
除了GFAP,星形胶质细胞特异性分子,如谷氨酸转运体(glutamate transporter,EAAT)-1、EAAT-2和谷氨酰胺合成酶(glutamine synthetase,GS)均在重度抑郁症患者脑中表达水平下降,同时伴随星形胶质细胞数量的减少[31]。EAAT-1和EAAT-2是星形胶质细胞摄取细胞外L-谷氨酸进入细胞内的主要途径,EAAT-1和EAAT-2表达下调可能损害L-谷氨酸的周转,从而导致抑郁症。已有研究表明,星形胶质细胞中EAAT的表达或活性的调节多发生在转录和转录后过程[32]。基因芯片分析表明,抑郁个体的蓝斑和特定皮质中与谷氨酸稳态相关的几种蛋白质的表达水平发生了显著变化,其中一些蛋白特属于星形胶质细胞[31-33]。实验研究表明,可以通过GLT-1抑制剂双氢红藻氨酸盐(dihydrokainic acid,DHK)阻断星形胶质细胞对谷氨酸的摄取而诱导出抑郁样表型,经过这样的处理后,动物可出现抑郁症的常见症状:快感缺乏和认知功能障碍[34]。另一组类似的研究表明,DHK注射到大鼠杏仁核后,大鼠社会交往减少[35]。该小组还证明了通过胶质细胞/神经元转运受体拮抗剂L-反式吡咯烷二羧酸(L-trans-pyrrolidine-2, 4-dicarboxylic acid,PDC)慢性阻断杏仁核中谷氨酸的摄取,会导致社会探究行为呈剂量依赖性降低和昼夜活动模式扰乱,这些与心境障碍症状一致[35]。星形胶质细胞中谷氨酸的异常调控还包括抑郁症动物模型中的神经胶质细胞GLAST的表达下调[36]。连续给予小鼠糖皮质激素受体(glucocorticoid receptor,GRS)特异性激动剂地塞米松(dexamethasone,DEX)21 d后,小鼠产生抑郁样行为,且小鼠前额叶皮质和海马中的GLAST mRNA表达减少[37]。Banasr等[38]用慢性不可预见性应激动物模型,研究表明,慢性应激会导致动物出现抑郁样行为表型和前额叶皮质神经胶质细胞的新陈代谢受损。有趣的是,应激诱导的细胞代谢和行为的改变可由谷氨酸调制药物利鲁唑治疗逆转。利鲁唑主要用于治疗肌萎缩侧索硬化症,认为其可通过对谷氨酸能神经传递的调控起到神经保护作用。虽然星形胶质细胞形态和功能改变的机制仍有待阐明,但利鲁唑对抑郁样行为的作用表明,调节星形胶质细胞中的谷氨酸周转是一种新型的抑郁症治疗策略。由于星形胶质细胞对谷氨酸稳态的关键作用,并且有实验证据表明抗抑郁药物能够影响各种胶质特定的EAAT的表达水平[39],因此针对谷氨酸能神经传递的药物是目前热门的候选新型抗抑郁药[40]。
对重度抑郁症患者的研究提示了星形胶质细胞缝隙链接主要成分CX43蛋白(connexin-43)与抑郁症之间的关系。CX43蛋白在重度抑郁症患者脑中表达减少[33, 41-42]。抑制CX43蛋白介导的缝隙链接信息交流能够引发啮齿类动物产生抑郁样行为[43]。除了分泌神经营养因子,星形胶质细胞中CX43蛋白表达的增加也可能是临床上抗抑郁药物产生疗效的新机制。Sun等[43]发现氟西汀和度洛西汀增加大鼠脑组织中CX43蛋白的表达。此外,在体外培养的星形胶质细胞中,阿米替林能够通过单胺依赖的机制增加CX43蛋白表达[44]。然而,近来也有不同报道,Jeanson等[45]运用原代培养的星形胶质细胞检测了7种抗抑郁药物对CX43蛋白表达以及两个连接蛋白通道功能的影响,研究发现,在无毒性作用的临床相关浓度下,7种抗抑郁药对CX43蛋白的表达均没有影响,但在CX43蛋白的缝隙连接通道信息交流以及半通道的功能方面,不同的抗抑郁药物有不同的作用,其中丙咪嗪、瑞波西汀和度洛西汀不影响缝隙连接的信息交流,阿米替林、氟西汀和文拉法辛对缝隙连接的信息交流有抑制作用,帕罗西汀则有增强的作用;氟西汀、帕罗西汀和度洛西汀能完全抑制CX43蛋白半通道功能,阿米替林、丙咪嗪、瑞波西汀以及文拉法辛则对半通道功能的抑制较为温和。
AQP-4负责从血液和脑进行水的双向输送。AQP-4基因敲除会导致产生与情绪障碍相关的认知功能障碍和神经营养因子依赖的可塑性的改变[46]。Kong等[47]研究发现,星形胶质细胞AQP-4的表达缺失会加重抑郁样行为,同时伴随星形胶质细胞数量和海马神经再生的减少。临床工作表明抑郁症与脑血管病相互影响,有研究发现脑血管病变患者前额叶皮质血管上AQP-4阳性的星形胶质细胞突触终扣覆盖减少,提示星形胶质细胞突触终钮形态的改变或者AQP-4分布的改变可能是脑血管病变患者产生抑郁表型的原因[48]。星形胶质细胞形态的改变是抑郁症患者大脑尸检时的一个显著特征[22],近期研究表明抗抑郁药对星形胶质细胞突起可塑性的增强作用需要AQP-4[49],提示AQP-4可能是改变星形胶质细胞病理状态的一个药物靶点,从而改善星形胶质细胞病理学改变相关的疾病,如抑郁症。
3 星形胶质细胞对神经再生的影响神经元和神经胶质细胞的再生不局限于发育中的大脑,在成人大脑的一些区域也有发生,主要是海马、侧脑室室下区(subventricular zone,SVZ)。许多研究试图寻找神经系统疾病和成人脑细胞再生失调之间的关系。海马神经发生的减少参与抑郁症的发病机制,并且是抗抑郁药的一个潜在作用靶点[50]。有研究认为抗抑郁治疗促进成人海马齿状回神经发生可能是抗抑郁药产生治疗效果的原因之一[51]。星形胶质细胞可能在这个过程中起着重要的作用,因为前体细胞产生的新生神经元事实上是放射状星形胶质细胞[52]。此外,邻近的星形胶质细胞还可以通过释放各种生长和神经营养因子调节成年神经发生。一项体外研究表明,抗抑郁药,丙咪嗪、氟西汀和文拉法辛能诱导人星形胶质细胞成熟分化表达多种神经元特异性标志物,即使它们具有了神经元表型[53]。也有证据表明,抗抑郁药可影响体外[54]和体内[29]星形胶质细胞的形态,但这些研究结果需要通过实验进一步证实。最近的动物模型研究也表明星形胶质细胞再生参与抑郁症的发病机制。嗅球摘除可引起大鼠抑郁样行为改变,Keilhoff等[54]研究表明,嗅球切除降低海马和SVZ神经前体细胞的增殖,可通过抗抑郁药丙咪嗪逆转该现象。同样,慢性社会应激降低了大鼠海马星形胶质细胞的数量和细胞体积,氟西汀可以逆转这一影响[29]。相反,一种有效治疗严重抑郁症的方法——电休克,会刺激大鼠海马和前额叶皮质中星形胶质细胞的增殖[55]。这些研究发现了星形胶质细胞再生参与抑郁症发病机制。
4 小结与展望大量的实验证据支持星形胶质细胞在抑郁症病理生理过程中的重要功能,星形胶质细胞已经成为抗抑郁药物筛选的靶点[32]。虽然在抑郁症患者的大脑中一般观察不到神经元的变性,但是发现有神经递质传递紊乱、脑发育异常以及突触结构的重塑等现象。此外,在抑郁症患者大脑中可观察到星形胶质形态和功能的变化[23, 25, 31, 56],星形胶质细胞除了在脑发育过程中对神经再生和突触形成有重要作用外,它在突触递质传递过程中也起到了重要作用[57]。许多研究开始尝试阐明星形胶质细胞在精神障碍中的功能作用和星形胶质细胞功能障碍在抑郁症发病机制中的作用。星形胶质细胞已被作为抑郁症新的药物靶点。与神经元相比,越来越多的证据支持胶质细胞在精神疾病中的重要性,但是仍有许多与星形胶质细胞有关的问题需要进一步阐明,包括星形胶质细胞的亚型分类、各脑区中星形胶质细胞的不同特征、发育中和成年大脑中胶质细胞再生以及胶质细胞相关调控因子等。对于这些问题的进一步研究可能会给情感障碍的治疗带来更多的新的药物靶点。
此外,异常的神经网络可能是抑郁症的神经生物学基础。个体生活早期关键时期中的应激事件和不利的环境经验塑造了异常的神经网络,导致个体在以后的生活中更容易受到应激事件的影响。应激事件以及青春期的发育变化可能会重新激活和加强皮质神经网络的不利重组,从而逐渐诱发全面的临床症状[58]。心理咨询、抗抑郁药物治疗以及行为调整可以重塑紊乱的神经网络,最终使得个体以健康且合适的行为应对环境。在这个过程中,星形胶质细胞很可能不仅仅是被动的提供支持,而是可能积极的引导其发生和发展,但还需进一步的实验研究来证实。
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