ISSN 1671-3710
CN 11-4766/R
主办：中国科学院心理研究所
出版：科学出版社

心理科学进展, 2018, 26(11): 1992-2002 doi: 10.3724/SP.J.1042.2018.01992

研究前沿

Parvalbumin阳性中间神经元缺陷在精神分裂症病理机制中的作用

邓潇斐1,2, 郭建友,1

1 中国科学院心理研究所 心理健康院重点实验室, 北京 100101

2 中国科学院大学, 北京 100049

Roles of impaired parvalbumin positive interneurons in schizophrenic pathology

DENG Xiaofei1,2, GUO Jianyou,1

1 Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, China

2 University of Chinese Academy of Sciences, Beijing 100049, China

通讯作者: 郭建友 E-mail:guojy@psych.ac.cn

收稿日期: 2017-12-4   网络出版日期: 2018-11-15

基金资助: * 国家自然科学基金资助(30800301)
* 国家自然科学基金资助(31170992)
* 国家自然科学基金资助(31371038)

Received: 2017-12-4   Online: 2018-11-15

摘要

精神分裂症是一种多发于青壮年的重性精神病, 其原因尚不明确。经典的多巴胺缺陷理论假说在某些方面欠缺解释力; 与此同时, 关于Parvalbumin阳性的中间神经元(后简称PV+神经元)缺陷在精神分裂症病理机制中的作用逐渐明晰, 并引起了越来越多的关注。PV+神经元在绝大部分脑区中是一种快速放电的抑制性神经元, 参与了突触可塑性的调节, 兴奋/抑制平衡的维持和神经发生等。而在精神分裂症中, PV+神经元的异常在患者和动物研究中都被普遍证实, 并发现与 NMDA受体缺陷、gamma波异常和氧化应激存在某些关联。

关键词： 精神分裂症; 中间神经元; NMDA受体; 氧化应激

Abstract

Schizophrenia is a severe mental disorder typically began in late adolescence or early adulthood. To date, the cause of schizophrenia remains largely unclear. The classical dopamine hypothesis of schizophrenia is now thought to be sided. Meanwhile, the involvement of impaired Parvalbumin positive interneurons (PV+ neurons) in the pathological mechanism of schizophrenia has been realized and received increasing attention. Generally, PV+ cells is a kind of inhibitory, fast-spiking interneurons, which had been demonstrated to be involved in synaptic plasticity, excitation/inhibition balance and neurogenesis. In schizophrenia, abnormal PV+ neurons has been commonly found in patients and relevant animal models., In this article, we reviewed the roles of deficits of PV+ neurons in schizophrenic pathology combined its principal phenotypes including defective NMDA receptors, abnormal gamma oscillation and oxidative stress, hoping to contribute to further investigation and development of new drugs.

Keywords： schizophrenia; interneurons; NMDA receptors; oxidative stress

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本文引用格式

邓潇斐, 郭建友. Parvalbumin阳性中间神经元缺陷在精神分裂症病理机制中的作用. 心理科学进展, 2018, 26(11): 1992-2002 doi:10.3724/SP.J.1042.2018.01992

DENG Xiaofei, GUO Jianyou. Roles of impaired parvalbumin positive interneurons in schizophrenic pathology. Advances in Psychological Science, 2018, 26(11): 1992-2002 doi:10.3724/SP.J.1042.2018.01992

1 前言

精神分裂症是一种重性精神病, 多在青壮年时期发作, 是世界上十大致残或使人丧失劳动能力的疾病之一, 同时也是各种精神疾病中患病率最高的一种, 其临床表现症状各异, 涉及感知觉、思维、情感和行为等多方面的障碍以及精神活动的不协调, 包括幻想、妄想、偏执和/或精神错乱等阳性症状, 以及持续的进行性的感情淡漠、注意力不集中、社交回避、认知缺损等阴性症状。

目前精神分裂症产生的病因并不十分明确, 科学家们通过临床用药经验和各种实验证据来探索精神分裂症产生的原因, 进而提出各种假说, 主要包括：多巴胺系统功能亢进假说(Davis & Kahn, 1991; Howes & Kapur, 2009)、γ-氨基丁酸(GABA)系统缺陷导致的兴奋/抑制不平衡假说(Lewis, Hashimoto, & Volk, 2005)、NMDA (N-methyl-D- aspartic acid)受体缺陷假说(Jentsch & Roth, 1999; Tsai & Coyle, 2002)以及5-羟色胺(5-HT)受体异常假说等等(Breier, 1995; Abi-Dargham, Laruelle, Aghajanian, Charney, & Krystal, 1997)。其中, 多巴胺假说基于经典的多巴胺受体拮抗类药物对精神分裂症治疗有效的观察而提出, 并获得了大量实验数据的支持, 因而成为精神分裂症病理原因最经典的解释。但必须指出, 解剖学研究中并没有发现多巴胺系统相关脑区和受体的病变, 提示多巴胺系统本身可能并非诱发精神分裂症的根本原因(Gothelf et al., 2000)。

近年来, 精神分裂症研究领域的另一个假说——大脑GABA系统缺陷假说逐渐引起了领域内研究者们的注意。其中, GABA能的小清蛋白阳性(parvalbumin positive, PV+)的中间神经元独特的性质和作用而备受关注(Cohen, Tsien, Goff, & Halassa, 2015)。PV+神经元是一种快速放电的局部中间神经元, 其能够通过各种微环路构成的神经网络对同区域的锥体神经元及其他中间神经元进行调控(Hu, Gan, & Jonas, 2014; Tremblay, Lee, & Rudy, 2016), 还有证据表明, PV+神经元参与了突触可塑性(Caillard et al,. 2000; Donato, Rompani, & Caroni, 2013), 并在脑发育(尤其在视觉发育)关键期发挥了重要作用(Fagiolini et al., 2004; Katagiri, Fagiolini, & Hensch, 2007; Kuhlman et al., 2013; He et al., 2014; Gu et al., 2016)。近期许多研究表明, PV+神经元在精神分裂症中扮演了重要角色(Cohen et al., 2015; Steullet et al., 2017)。本文综述了目前PV+神经元对精神分裂症影响的相关研究, 以期对了解该疾病的内在机制并开展进一步的研究提供借鉴。

2 PV+神经元的介绍

若以还原论的视角尽可能简单地描述大脑神经网络, 其主要由两种类型的神经元组成：提供兴奋性神经冲动的谷氨酸能主神经元(Glutamate principal neurons)和拥有抑制功能的γ-氨基丁酸能中间神经元(GABAergic interneurons)。纵观全脑, 虽然GABA能中间神经元仅占神经元总量的10%~20% (Freund & Buzsáki, 1996; Aika, Ren, Kosaka & Kosaka, 1994; Halasy & Somogyi, 1993), 但由于其多样化的形态结构与生理功能, 因而在调节、整合神经网络信号中发挥了极其重要的作用。此外, GABA能中间神经元的功能受损也是导致各种遗传发育及精神类疾病的主要原因(Marín, 2012)。

90年代以来, 很多实验室开始研究一类特定的中间神经元：快速放电的小清蛋白阳性表达中间神经元(the fast-spiking parvalbumin-positive interneuron)。小清蛋白作为具有保守结构的酸性蛋白超家族的一员, 是一种小分子量(一般为9~ 11 kDa)的钙离子绑定蛋白(Calcium binding protein, CaBP)。PV中间神经元可根据其形态分为多种亚型, 并分别与锥体神经元的特定部位形成突触。其中最常见的是篮状细胞(Basket cell)和吊灯状细胞(Chandelier cell), 前者约占PV中间神经元总量的90%, 主要投射到锥体神经元的胞体和近端树突; 后者则只与锥体神经元的轴突起始部位形成突触。由于PV+神经元的轴突所靶向的细胞结构是锥体细神经元对输入信息作出反应并发放动作电位的关键部位, 因此PV+神经元对锥体神经元能否产生动作电位以及动作电位发放的时相起着重要的调控作用。

一般来说, PV阳性神经元通常是GABA能的。Celio和Heizmann (1981)通过免疫荧光双标GAD (一种GABA能神经元的免疫标记物)和PV, 证实PV阳性的神经元分布和GABA能神经元的分布有很高的一致性, 在大脑皮层中, 几乎所有的PV+神经元都是GABA能的, 同时, 70-80%的GABA能神经元含有PV。在海马的CA1区, 11%的神经元是GABA能的, 而这些GABA能神经元中24%是PV+神经元(Bezaire & Soltesz, 2013)。然而近年来有越来越多的证据表明, 谷氨酸能的PV阳性神经元不仅存在, 而且在神经系统中扮演了重要角色。例如, 最近有研究证明上丘中表达的PV的兴奋性投射神经元是参与激发“战斗-逃跑”反应的关键神经元亚型(Shang et al, 2015)。

20年前, 这种中间神经元的性质完全不为人知。20年后, 受益于膜片钳、同步多细胞记录、光遗传、钙离子成像等等技术的广泛使用, 我们对PV中间神经元的认识变得比其他几种中间神经元要更多。它们不仅参与了基础的微环路功能, 例如前馈抑制和反馈抑制(Buzsàki & Eidelberg, 1981; Miles,1990; Pouille & Scanziani, 2001, 2004), 或gamma震荡波的产生(Bartos, Vida & Jonas, 2007; Cardin et al, 2009; Sohal, Zhang, Yizhar, & Deisseroth, 2009; Stark et al, 2013); 还参与了复杂的神经网络运作, 例如大脑发育“关键期”突触可塑性的调控(He et al., 2014)以及感知反应的增益调节(Hu et al., 2014)等等。此外, PV+神经元也在多种脑疾病中扮演重要角色(例如癫痫、自闭症、精神分裂症), 因此也是很多临床脑疾病的未来的治疗的潜在方向。

3 PV+中间神经元与精神分裂症

3.1 与精神分裂症相关的PV+中间神经元变化

精神分裂症最显著表现就是前额叶(Lewis et al., 2005)和海马(Zhang & Reynolds, 2002)的GABA系统的改变。具体表征有GAD67表达和PV+神经元数量减少(Todtenkopf & Benes, 1998; Hashimoto et al., 2003)。例如, 在精神分裂症患者的尸检研究, 发现了几个脑区中PV+神经元选择性地减少, 包括内侧前额叶(medial prefrontal cortex, mPFC)、丘脑、内嗅皮层(entorhinal cortex)和海马前部(Beasley & Reynolds, 1997; Bitanihirwe, Lim, Kelley, Kaneko, & Woo, 2009; Pantazopoulos, Woo, Lim, Lange, & Berretta, 2007; Zhang & Reynolds, 2002)。其中以海马的相关报道最为常见, Zhang和Reynolds (2002)甚至在精神分裂症患者海马的所有亚区都发现了PV中间神经元密度的降低, 而作为对照的另一种GABA能的中间神经元—— Calretinin+神经元的密度则不受影响。近年来, 很多证据都将海马定位为精神分裂症发病的中枢, 甚至是始发脑区, 其他脑区的变化可能只是海马病变的次级效应。该理论认为, 海马前部GABA能中间神经元(主要是PV+神经元)的功能失调极大地削弱了对该脑区的抑制控制, 兴奋/抑制的平衡被打破, 从而导致其活动水平异常增强(Behrens & Sejnowski, 2009; Lodge, Behrens, & Grace, 2009; Grace, 2012)。例如, 对精分患者的功能性成像揭示了其海马的过度激活(Malaspina et al., 1999; Medoff, Holcomb, Lahti & Tamminga, 2001; Heckers, 2004; Schobel et al., 2009; Kraguljac, White, Reid & Lahti, 2013)。

PV缺陷在精神分裂症的动物模型中也得到了印证。例如, 在精神分裂症的MAM模型中, 在母鼠怀孕第15天腹腔注射神经毒素甲基氧化偶氮甲醇(methylazoxymethanol, MAM)诱发子代出现精神分裂样症状, 发现MAM注射会导致成年后的子代腹侧海马的的PV+神经元特异性地丧失(Lodge et al., 2009)。此外, 在精神分裂症的polyribocytidilic (polyIC)模型(给怀孕17天的孕鼠注射polyIC)中, 也出现了mPFC和vHPC的PV+神经元减少的现象以及安非他明诱发的运动增强(Meyer, Nyffeler, Yee, Knuesel & Feldon, 2008)。

此外, 包括精神分裂症在内的许多精神疾病还伴随着异常的神经发生(neurogenesis), 由于抑制性神经递质GABA在神经发生的各个阶段均发挥着重要的作用, 包括PV+神经元在内的GABA能中间神经元的缺陷很有可能是导致此类疾病中神经发生异常的原因。有文献报道在海马的齿状回颗粒细胞下层(subgranular zone,SGZ)的PV+神经元能够调控新生神经元的分裂成熟、树突的发育及突触整合(Ge et al., 2006; Song et al., 2013)。Song等人(2013)利用光遗传技术发现PV+神经元特异地对I型细胞的增殖和自我更新具有调控作用。此外, PV+神经元还能影响新生神经元的存活, Wang等(2014)发现敲除PV阳性中间神经元的淀粉样前体蛋白(amyloid precursor protein, APP)可以影响突触周围GABA的含量, 进而减少海马齿状回区新生颗粒细胞(DGCs)的存活。

因此, PV+神经元功能功能的健全与否关系到中枢神经系统的兴奋/抑制平衡的维持和神经发生的正常进行, 因而成为包括精神分裂症在内的众多精神病领域的热门研究对象(Kobayashi & Buckmaster, 2003; Gogolla et al., 2009; Burguière, Monteiro, Feng & Graybiel, 2013; Steullet et al., 2017)。下文将以精神分裂症中PV+神经元的异变为锚点, 结合精分研究领域中最常见的三种病理表征(NMDA受体缺陷、gamma波异常和氧化应激), 进一步介绍PV+神经元在精神分裂症中的作用。

3.2 精神分裂症的gamma波异常与PV+神经元缺陷

Gamma波缺陷常见于精神分裂症的相关研究中, 是其重要的症状表型之一。在对精神分裂症患者的研究中, Gamma波异常的具体表现形式呈现多样性, 包括波幅降低(Haig et al., 2000; Kwon et al., 1999)和增加(Demiralp et al., 2006; Flynn et al., 2008; Barr et al., 2010), 以及特定频段的gamma波减少(Spencer et al., 2003; Spencer, Niznikiewicz, Shenton, & McCarley, 2008; Uhlhaas et al., 2006)等等, 考虑到上述研究都是事件相关的, 出现这种多样性可能是所采用的认知任务本身的不同所导致的(Hunt, Kopell, Traub, & Whittington, 2017)。同样的, 精神分裂的易感基因模型也表现出gamma波缺陷, 比如Neuregulin, erbB4和calcineurin等基因的突变在诱发小鼠精分样行为的同时, 伴随了gamma波的增加(Del Pino et al., 2013; Fisahn, Neddens, Yan, & Buonanno, 2008; Suh, Foster, Davoudi, Wilson, & Tonegawa, 2013)。

由于Gamma神经振荡的产生需要对主神经元产生强烈的协同性抑制(Gonzalez-Burgos & Lewis, 2008), 精神分裂中常见的GABA神经传递的缺陷被认为是导致gamma异常的潜在机制(Lewis, Curley, Glausier, & Volk, 2012); 鉴于PV+神经元是gamma荡波形成的关键因素(Bartos et al, 2007; Cardin et al, 2009; Stark et al, 2013), 且又是在精神分裂症中突触传递功能受损最严重(荧光原位杂交中检测到丢失GAD67 mRNA最多)的GABA能中间神经元亚型(Hashimoto et al., 2003), 提示二者在精神分裂症中存在紧密的联系, 并得到了相关实验证据的支持——在精神分裂症的动物研究中, 就多次观察到PV表达和gamma波的同步减少(Cunningham et al., 2006; Lodge et al, 2009; Steullet et al., 2010)。因而大量的研究者认为, 精神分裂症中常见的PV+神经元受损或许能为该疾病状态下执行认知任务时不正常的gamma波提供合理的解释(Lewis et al., 2012; Volk, Gonzalez- Burgos, & Lewis, 2016; Uhlhaas & Singer, 2010)。譬如说, Kim, Ährlund-Richter, Wang, Deisseroth和Carlén(2016)揭示了内侧前额叶的PV+神经元介导的gamma波是产生自上而下注意的关键因素, 可能是包括精神分裂症在内的多种精神疾病中广泛存在的注意力缺陷的内在病理机制。值得注意的是, 前文提到PV+神经元可根据结构分为两种亚型, 有研究者认为是PV+神经元的篮状细胞, 而不是吊灯状细胞的突触前或突触后的变化导致了精神分裂中的gamma波的紊乱和认知损伤(Lewis et al., 2012; Gonzalez-Burgos & Lewis, 2012), 但由于目前尚无法在细胞层面对这两种PV+神经元亚型进行分别的操纵, 因此还没有最直接的证据。

3.3 精神分裂症的NMDA受体缺陷与PV+神经元缺陷

NMDA受体缺陷假说也是精神分裂症的经典假说之一, 自Luby等人(1959)发现NMDA受体拮抗剂PCP (phencycline)可以在正常人身上引发类似精神分裂症样的行为表征后, 该假说在精神分裂症领域一直备受关注。在此之后, 包括PCP在内的很多NMDA受体拮抗剂(例如APV, CPP, MK-801和Ketamine)陆续被发现能够引发精神分裂症样症状, 并被应用于精神分裂症研究的动物造模中(Javitt & Zukin, 1991; Krystal et al., 1994; Olney & Farber, 1995)。

很多证据表明NMDA受体与PV+神经元之间存在密切的关系。NMDA受体被发现能够干预中枢神经系统中GAD67和PV的表达(Kinney et al., 2006; Romón & Adell, 2011; Abekawa, Ito, Nakagawa, & Koyama, 2007), 影响PV+神经元的抑制性突触传递(Zhang, Behrens, & Lisman, 2008), 还可以调节其放电特性(Albéri, Lintas, Kretz, Schwaller, & Villa, 2013)与突触可塑性(Caillard et al., 2000)。此外, 有证据表明NMDA受体的NR2A亚基在PV+神经元中可能扮演重要角色, 通过单细胞分离mRNA测定不同类型细胞中NR2A/NR2B的比率, 发现PV+神经元中NR2A/NR2B的mRNA表达量之比是锥体神经元的五倍, 进一步的药理实验揭示了NR2A而不是NR2B的选择性拮抗剂减少了PV的表达(Kinney et al., 2006)。

考虑到精神分裂症中普遍报道的PV+神经元缺陷, 上述研究暗示NMDA受体受损可能是导致精神分裂症中PV+神经元结构和功能异常的关键因素。换句话说, PV+神经元受损在精神分裂症中可能是NMDA受体功能失调的二级效应。NMDA受体功能不全导致PV+神经元更难以被兴奋, 由于PV+神经元是重要的抑制性神经元, 其在局部神经微环路中角色的缺失会直接引起锥体神经元的兴奋性的增加, 使得神经网络去抑制, 从而导致大脑兴奋/抑制水平的失衡, 进而引发精神疾病(Cohen et al., 2015; Lisman et al.,2008)。最直观的证据来自转基因动物的研究, 例如, Belforte等人(2010)发现, 在敲除NMDA受体诱发出GAD67和PV表达下调的同时, 动物还表现出精神分裂症样的行为。而在PV+神经元中特异性地敲除NR1亚基的基因(使得NMDA受体无法在PV+神经元中表达), 会导致该转基因动物表现出脑电波异常(Carlen et al., 2012; Korotkova, Fuchs, Ponomarenko, von Engelhardt, & Monyer, 2010; Billingslea et al., 2014; Gonzalez-Burgos & Lewis, 2012), 认知功能受损(Carlen et al., 2012; Korotkova et al., 2010), 社交障碍(Saunders et al., 2013; Billingslea et al., 2014)等精神分裂症中常见的症状表现。

与此同时, 精神分裂症中Gamma波的异常也间接佐证了上述推测。前文提到, PV+神经元是参与Gamma波形成的必要条件(Sohal et al., 2009; Bartos et al., 2007; Cardin et al, 2009; Stark et al, 2013), 而gamma波异常又是精神分裂症的常见表型(Bartos et al., 2007; Klausberger & Somogyi, 2008; Cardin et al., 2009; Lodge et al., 2009)。在此基础上, 一些研究者采用药理阻断或者基因删除的方式来操控PV+神经元中的NMDR受体, 成功干扰了Gamma波(Lisman et al., 2008; Gonzalez- Burgos & Lewis, 2012; Korotkova et al., 2010; Carlen et al., 2012; Kocsis, 2012), 证明了PV+神经元中的NMDR受体的确在gamma波的形成中起到重要作用, 其功能紊乱可能是精神分裂症中gamma波异常的潜在病理原因之一。值得注意的是, 上述实验结果可能存在发育阶段的特异性：只表现在出生后早期删除NMDA受体的动物身上, 而不能表现在青春期后删除NMDA受体的动物上(Belforte et al., 2010); 这说明NMDA受体不仅参与协同局部微环路的神经振荡, 而且对PV+神经元生理功能的发育成熟是必不可少的(Cohen et al., 2015)。

3.4 精神分裂症氧化应激上调与PV+神经元缺陷

氧化应激(oxidative stress), 指的是人体在异常状态下, 氧化和抗氧化机制失衡, 导致过量的自由基对神经元和大脑的损害作用, 它与神经炎症关联紧密。而在精神分裂症中, 大脑的氧化应激/氧化还原机能的紊乱已被多次证明, 并逐渐成为领域内的共识(Do, Cabungcal, Frank, Steullet, & Cuenod, 2009; Flatow, Buckley, & Miller, 2013; Yao & Keshavan, 2011; Steullet et al., 2017), 最近, 有研究者(Kim et al., 2016)利用磷磁共振波谱(Phosphorus magnetic resonance spectroscopy, P-MRS)进行NAD+/NADH的检测, 首次在人类身上证明了精神分裂症的抗氧化机能失调。大脑抗氧化机能的失调包括脑内谷胱甘肽(glutathione, GSH) 的减少(Do et al,2009), 由于GSH是主要的内源性抗氧化剂和氧化还原反应的调节剂, 其合成缺陷会导致小鼠腹侧海马的CA3和齿状回的PV+神经元选择性地减少, 并伴随着β/γ神经震荡的减少, 并引起相关的精神病样行为症状(Steullet et al., 2010)。

精神分裂症中的PV+神经元损伤和过度的氧化应激之间存在重要联系, 许多精分相关的环境风险因素/早期应激源能够干扰抗氧化系统, 增加氧化应激(Do et al., 2009)和神经炎症(Brenhouse & Andersen, 2011; Gárate et al., 2013; Kaur, Rathnasamy, & Ling., 2013), 并且减少前额叶和海马的PV表达(Dell'Anna, Geloso, Magarelli & Molinari, 1996; Harte, Powell, Swerdlow, Geyer, & Reynolds, 2007; Meyer et al, 2008; Brenhouse & Andersen, 2011; Komitova et al., 2013)。虽然上述研究并没有阐明二者之间的因果关系, 但种种迹象表明, 氧化应激是导致PV+神经元损伤的重要原因。

首先, 在时间顺序上, 氧化应激发生在PV+神经元呈现缺陷之前(Steullet et al., 2010); 其次, 在多种精神分裂的动物模型中都证实了, 抗氧化应激药物对PV+神经元的起到了有效的保护作用(Cabungcal, Steullet, Kraftsik, Cuenod & Do, 2013; Behrens et al., 2007; Schiavone et al., 2009; Cabungcal et al., 2014; Jiang, Rompala, Zhang, Cowell, & Nakazawa, 2013)。为了进一步验证氧化应激诱发的PV+神经元缺陷是否是精神分裂症的普适性病理原因, 最近Steullet等人(2017)在多达9种精神分裂症模型动物(大体可分为基因模型、损毁模型、药理模型和环境模型)的前扣带回(ACC)中免疫共染了PV、PNN (环神经元周围网, Perineuronal nets)和8-oxo-dG (氧化应激的标记物), 结果发现, 除了两种模型动物没有表现出以上三种标记物的任何改变, 在其余的动物中, PV+神经元缺陷必然伴随着不同程度的氧化应激。综上, 我们可以得出结论, 由过度的氧化应激引发的PV+神经元缺陷在精神分裂症中是一个普遍现象, 它可能是该疾病的大多数易感因素(包括药物、环境、基因等)最终诱发精分表型的“必经之路”。

然而, 上述结论引申出了另一个重要的问题：过度的氧化应激是如何选择性地损伤PV+神经元, 而不是其他神经细胞呢?精神分裂症中可普遍观察到的PNN的异常变化为我们提供了参考答案(Steullet et al., 2017; Mauney et al., 2013; Pantazopoulos, Woo, Lim, Lange, & Berretta, 2010)。PNN是一种具有细胞特异性的胞外基质(extracellular matrix)结构, 它主要包裹在PV+神经元的胞体和近端神经突(Rossier et al., 2015)。有证据表明PNN是保护PV+神经元不受氧化应激损伤的重要结构(Cabungcal et al., 2013), 因此精神分裂症中的PV+神经元缺陷可能是由于PNN异常导致PV 神经元失去对氧化应激的防御机制所引发的次级效应(Cohen et al., 2015)。

4 总结和展望

尽管精神分裂症已经被研究多年, 相关假设和实验结果层出不穷, 然而我们对其病理机制仍然不是很清楚。在其中, PV+神经元缺陷只是该疾病众多神经生理变化的其中一隅, 然而近年来的种种实验证据都最终指向了PV+神经元异常, 提示PV+神经元在该疾病中可能扮演重要角色。因此, 本文立足于PV+神经元的基本结构功能及其在精神分裂症中的缺陷, 对其在精神分裂症中的改变及其相关的实验证据进行了综述, 以期为相关研究的深入探索提供借鉴和支持。

包括PV+神经元在内的中间神经元之间存在着复杂而重要的相互作用, 它们和主神经元一起构建了精细的神经微环路系统, 共同决定了大脑认知功能的正常运行(Wolff et al., 2014; Markram et al., 2004)。在其中, PV+神经元是被研究得最多的一种GABA能中间神经元, 这一方面是因为它是皮层中最多的中间神经元(占中间神经元总数的40%) (Tremblay et al., 2016), 另一方面则是因为其快速高频放电的特性而在电生理记录中更具有区分度。而在精神分裂症中, PV+神经元也比其他中间神经元受到了更多的关注, 这种偏爱的理由其实依然基于上述两个方面, 这种惯性使得大多数精神分裂症研究中所指出的PV缺陷的结果缺乏特异性。尽管有充足的证据表明, 精神病患者的大脑表现出PV、SOM和CCK表达的同步下调, 暗示了多种中间神经元亚型在该疾病中的参与(Morris, Hashimoto & Lewis, 2008; Konradi et al., 2011), 但我们仍然不清楚其它中间神经元(比如SOM+神经元, VIP+神经元)是如何参与了精神分裂症, 是否也和gamma缺陷, NMDA受体异常和氧化应激, 以及其它认知和生理上的病变存在某种联系。鉴于以上原因, 未来的研究应试图阐明不同的中间神经元亚群在精神分裂症中的潜在机制和作用权重。

与此同时, 围绕PV+神经元突触前后相关受体为靶点进行的抗精神病药物的开发也在进行中, 目前的关注点主要集中在GABAA受体上, 尤其是α1-6亚基(Gill & Grace, 2014)。在新皮层和海马中, 含α5亚基的 GABAA受体位于PV+神经元突触后, 影响PV+神经元对锥体神经元的调控; 而含α1和α2/3 亚基的 GABAA受体则主要分布于PV+神经元突触前, 接收来自其他神经元的抑制性信号(Ali & Thomson, 2007)。其中又以 GABAA受体5α亚基最为瞩目, 已有药理实验表明5α GABAA受体激动剂能在一定程度上扭转精神分裂症相关的认知缺陷(Featherstone, Rizos, Nobrega, Kapur, & Fletcher, 2007; Gill, Lodge, Cook, Aras, & Grace, 2011; Gill & Grace, 2014)。尽管如此, 目前尚未有此类药物通过临床实验的报道, 但这仍不失为新的抗精神病药物开发的一个方向。

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Weak inhibition within visual cortex early in life prevents experience-dependent plasticity. Loss of responsiveness to an eye deprived of vision can be initiated prematurely by enhancing$\gamma-aminobutyric$acid (GABA)-mediated transmission with benzodiazepines. Here, we use a mouse "knockin" mutation to 伪 subunits that renders individual GABA type A (GABAA) receptors insensitive to diazepam to show that a particular inhibitory network controls expression of the critical period. Only$\alpha 1-containing$circuits were found to drive cortical plasticity, whereas$\alpha 2-enriched$connections separately regulated neuronal firing. This dissociation carries implications for models of brain development and the safe design of benzodiazepines for use in infants.

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Background: Schizophrenia is associated with impaired antioxidant defense, including abnormal serum, plasma, and red blood cell (RBC) oxidative stress parameters. We performed a meta-analysis of these associations, considering the effect of clinical status and antipsychotic treatment after an acute exacerbation of psychosis.Methods: We identified articles by searching PubMed, PsychInfo, and Institute for Scientific Information, and the reference lists of identified studies.Results: Forty-four studies met the inclusion criteria. Total antioxidant status seemed to be a state marker, because levels were significantly decreased in cross-sectional studies of serum and plasma in first-episode psychosis (FEP) and significantly increased in longitudinal studies of antipsychotic treatment for acute exacerbations of psychosis (p Conclusions: Oxidative stress abnormalities in FEP suggest an effect that might be independent of antipsychotic medications. Although some parameters (total antioxidant status, RBC catalase, and plasma nitrite) might be state markers for acute exacerbations of psychosis, others (RBC superoxide dismutase) might be trait markers; however, more longitudinal studies are needed. Our findings suggest that oxidative stress might serve as a potential biomarker in the etiopathophysiology and clinical course of schizophrenia.

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Recent studies have explored a model of the disconnection hypothesis of schizophrenia through the demonstration of abnormal stimulus induced gamma phase synchrony (GPS). These studies have principally examined synchrony in the 4002Hz band elicited in post-stimulus time periods, relative to a pre-stimulus baseline. In this study we examined the absolute magnitude of GPS elicited by a selective attention task, in first-episode psychosis (FEP). We hypothesized that FEP would be associated with abnormalities in absolute GPS, particularly when required to selectively attend to task-relevant stimuli. Fifty-five first-episode psychosis (FEP) subjects and one hundred and ten matched healthy control subjects underwent an auditory oddball selective attention task during EEG recording. The absolute magnitude of GPS was extracted for the range 35–4502Hz, and time-locked to stimulus onset. GPS averaged were computed for oddball ‘target’ (task-relevant) and ‘non-target’ (task-irrelevant) stimuli, for each subject. FEP subjects showed a significant elevation in absolute GPS relative to controls, apparent across the 35–4502Hz range. This elevation was most marked in the left centro-temporal region, across the 80002ms post-stimulus period. In FEP subjects, the elevation in GPS was also greater for target compared to non-target stimuli, while healthy controls did not show a stimulus effect. These findings complement previous evidence for reductions in peak gamma synchrony, calculated relative to a pre-stimulus baseline, in schizophrenia. The results an excess of absolute GPS in schizophrenia may contribute to an inability to effectively integrate task-relevant information, which underlie psychotic symptoms.

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One unifying explanation for the complexity of Autism Spectrum Disorders (ASD) may lie in the disruption of excitatory/inhibitory (E/I) circuit balance during critical periods of development. We examined whether Parvalbumin (PV)-positive inhibitory neurons, which normally drive experience-dependent circuit refinement (Hensch Nat Rev Neurosci 6:877鈥888, 1), are disrupted across heterogeneous ASD mouse models. We performed a meta-analysis of PV expression in previously published ASD mouse models and analyzed two additional models, reflecting an embryonic chemical insult (prenatal valproate, VPA) or single-gene mutation identified in human patients (Neuroligin-3, NL-3 R451C). PV-cells were reduced in the neocortex across multiple ASD mouse models. In striking contrast to controls, both VPA and NL-3 mouse models exhibited an asymmetric PV-cell reduction across hemispheres in parietal and occipital cortices (but not the underlying area CA1). ASD mouse models may share a PV-circuit disruption, providing new insight into circuit development and potential prevention by treatment of autism. The online version of this article (doi:10.1007/s11689-009-9023-x) contains supplementary material, which is available to authorized users.

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Phencyclidine (PCP, "angel dust") induces a psychotomimetic state that closely resembles schizophrenia. As opposed to amphetamine-induced psychosis, PCP-induced psychosis incorporates both positive (e.g., hallucinations, paranoia) and negative (e.g., emotional withdrawal, motor retardation) schizophrenic symptoms. PCP-induced psychosis also uniquely incorporates the formal thought disorder and neuropsychological deficits associated with schizophrenia. The purpose of the present paper is to review recent advances in the study of the molecular mechanisms of PCP action and to describe their implications for the understanding of schizophrenic pathophysiology. Twenty-five papers were identified that described the clinical dose and serum and CSF levels at which PCP induces its psychotomimetic effects. The dose range of PCP-induced effects were compared to the dose range at which PCP interacts with specific molecular targets and affects neurotransmission. It was found that PCP-induced psychotomimetic effects are associated with submicromolar serum concentrations of PCP. At these concentrations PCP interacts selectively with a specific binding site (PCP receptor) that is associated with the N-methyl-D-aspartate (NMDA)-type excitatory amino acid receptor. Occupation of its receptor by PCP induces noncompetitive inhibition of NMDA receptor-mediated neurotransmission. Other NMDA antagonists such as the dissociative anesthetic ketamine induce PCP-like neurobehavioral effects in proportion to their potency in binding to the PCP receptor and inducing NMDA receptor inhibition. These findings suggest that endogenous dysfunction of NMDA receptor-mediated neurotransmission might contribute to the pathogenesis of schizophrenia. The relative implications of the PCP and amphetamine models of schizophrenia are discussed in relationship to the diagnosis and etiology of schizophrenia.

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Saunders, J. A., Tatard‐Leitman, V. M., Suh, J., Billingslea, E. N., Roberts, T. P., & Siegel, S. J. ( 2013).

Knockout of NMDA Receptors in Parvalbumin Interneurons Recreates Autism‐Like Phenotypes

Autism Research, 6( 2), 69-77.

DOI:10.1002/aur.1264      URL     PMID:4064157      [本文引用: 1]

Autism is a disabling neurodevelopmental disorder characterized by social deficits, language impairment, and repetitive behaviors with few effective treatments. New evidence suggests that autism has reliable electrophysiological endophenotypes and that these measures may be caused by n-methyl-d-aspartic acid receptor (NMDAR) disruption on parvalbumin (PV)-containing interneurons. These findings could be used to create new translational biomarkers. Recent developments have allowed for cell-type selective knockout of NMDARs in order to examine the perturbations caused by disrupting specific circuits. This study examines several electrophysiological and behavioral measures disrupted in autism using a PV-selective reduction in NMDA R1 subunit. Mouse electroencephalograph (EEG) was recorded in response to auditory stimuli. Event-related potential (ERP) component amplitude and latency analysis, social testing, and premating ultrasonic vocalizations (USVs) recordings were performed. Correlations were examined between the ERP latency and behavioral measures. The N1 ERP latency was delayed, sociability was reduced, and mating USVs were impaired in PV-selective NMDA Receptor 1 Knockout (NR1 KO) as compared with wild-type mice. There was a significant correlation between N1 latency and sociability but not between N1 latency and premating USV power or T-maze performance. The increases in N1 latency, impaired sociability, and reduced vocalizations in PV-selective NR1 KO mice mimic similar changes found in autism. Electrophysiological changes correlate to reduced sociability, indicating that the local circuit mechanisms controlling N1 latency may be utilized in social function. Therefore, we propose that behavioral and electrophysiological alterations in PV-selective NR1 KO mice may serve as a useful model for therapeutic development in autism. Autism Res 2013, 6: 69 77. 2013 International Society for Autism Research, Wiley Periodicals, Inc.

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Involvement of NOX2 in the development of behavioral and pathologic alterations in isolated rats

Biological Psychiatry, 66( 4), 384-392.

DOI:10.1016/j.biopsych.2009.04.033      URL     [本文引用: 1]

Schobel, S. A., Lewandowski, N. M., Corcoran, C. M., Moore, H., Brown, T., Malaspina, D., Small, S. A. ( 2009).

Differential targeting of the CA1 subfield of the hippocampal formation by schizophrenia and related psychotic disorders

Arch. Gen. Psychiatry, 66( 9), 938-946

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A parvalbumin-positive excitatory visual pathway to trigger fear responses in mice

Science, 348( 6242), 1472-1477.

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Spencer, K. M., Nestor, P. G., Niznikiewicz, M. A., Salisbury, D. F., Shenton, M. E., & McCarley, R. W. ( 2003).

Abnormal neural synchrony in schizophrenia

Journal of Neuroscience, 23( 19), 7407-7411.

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Sensory-evoked gamma oscillations in chronic schizophrenia

Biological Psychiatry, 63( 8), 744-747.

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The early visual-evoked gamma oscillation (VGO) elicited by Gestalt stimuli is reduced in schizophrenia patients compared with healthy individuals, but it is unknown whether this effect is specific to these particular stimuli and task. In contrast, the early auditory-evoked gamma oscillation (AGO) was reported to be unaffected in a sample of unmedicated, mostly first-episode schizophrenics, but it is unknown whether this oscillation is abnormal in chronic, medicated patients. We investigated these issues by examining the VGO and AGO in chronic schizophrenic (SZ) and matched healthy control (HC) subjects. Subjects (21 HC, 23 SZ) performed visual and auditory oddball tasks. Visual stimuli were letters, and auditory stimuli were simple tones. Event-related spectral measures (phase locking factor and evoked power) were computed on Morlet wavelet-transformed single epochs from the standard trials. VGO phase locking at occipital electrodes was reduced in SZ compared with HC. In contrast, AGO phase locking and evoked power did not differ between groups. The VGO deficit may be a general phenomenon in schizophrenia, whereas the AGO evoked by simple tone stimuli does not appear to be abnormal in chronic, medicated schizophrenia patients.

Sohal, V. S., Zhang, F., Yizhar, O., & Deisseroth, K. ( 2009).

Parvalbumin neurons and gamma rhythms enhance cortical circuit performance

Nature, 459( 7247), 698-702.

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Parvalbumin interneurons mediate neuronal circuitry-neurogenesis coupling in the adult hippocampus

Nature Neuroscience, 16( 12), 1728-1730.

[本文引用: 2]

Stark, E., Eichler, R., Roux, L., Fujisawa, S., Rotstein, H. G., & Buzsáki, G. ( 2013).

Inhibition-induced theta resonance in cortical circuits

Neuron, 80( 5), 1263-1276.

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Steullet, P., Cabungcal, J. H., Coyle, J., Didriksen, M., Gill, K., Grace, A. A., ... Do, K. ( 2017).

Oxidative stress- driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia

Molecular Psychiatry, 22( 7), 936-943.

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Redox dysregulation affects the ventral but not dorsal hippocampus: impairment of parvalbumin neurons, gamma oscillations, and related behaviors

The Journal of Neuroscience, 30( 7), 2547-2558.

[本文引用: 3]

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Impaired hippocampal ripple-associated replay in a mouse model of schizophrenia

Neuron, 80( 2), 484-493.

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Suh et02al. demonstrate that sequential replay of hippocampal place cells during rest is abolished in a mouse model of schizophrenia, although place-dependent firing of those cells is normal, providing insight into information-processing impairments associated with the disorder.

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Distribution of glutamate decarboxylase65 immunoreactive puncta on pyramidal and nonpyramidal neurons in hippocampus of schizophrenic brain

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GABAergic interneurons in the neocortex: from cellular properties to circuits

Neuron, 91( 2), 260-292.

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Tremblay et聽al. review our current knowledge of the diversity of neocortical GABAergic inhibitory interneurons and discuss how the intrinsic properties of interneuron subtypes contribute to specific computational properties within various circuit motifs formed between inhibitory and excitatory neurons.

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Glutamatergic mechanisms in schizophrenia

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Dysfunctional long-range coordination of neural activity during Gestalt perception in schizophrenia

Journal of Neuroscience, 26(#31), 8168-8175.

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Abnormal neural oscillations and synchrony in schizophrenia

Nature Reviews. Neuroscience, 11( 2), 100-113.

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l-Proline, GABA synthesis and gamma oscillations in schizophrenia

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Wang, B., Wang, Z., Sun, L., Yang, L., Li, H., Cole, A. L., ... Zheng, H. ( 2014).

The amyloid precursor protein controls adult hippocampal neurogenesis through GABAergic interneurons

The Journal of Neuroscience, 34( 40), 13314-13325.

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Amygdala interneuron subtypes control fear learning through disinhibition

Nature, 509( 7501), 453-458.

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Yao, J.K., & Keshavan, M.S . ( 2011).

Antioxidants, redox signaling, and pathophysiology in schizophrenia: an integrative view

Antioxidants & Redox Signaling, 15( 7), 2011-2035.

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Schizophrenia (SZ) is a brain disorder that has been intensively studied for over a century; yet, its etiology and multifactorial pathophysiology remain a puzzle. However, significant advances have been made in identifying numerous abnormalities in key biochemical systems. One among these is the antioxidant defense system (AODS) and redox signaling. This review summarizes the findings to date in human studies. The evidence can be broadly clustered into three major themes: perturbations in AODS, relationships between AODS alterations and other systems (i.e., membrane structure, immune function, and neurotransmission), and clinical implications. These domains of AODS have been examined in samples from both the central nervous system and peripheral tissues. Findings in patients with SZ include decreased nonenzymatic antioxidants, increased lipid peroxides and nitric oxides, and homeostatic imbalance of purine catabolism. Reductions of plasma antioxidant capacity are seen in patients with chronic illness as well as early in the course of SZ. Notably, these data indicate that many AODS alterations are independent of treatment effects. Moreover, there is burgeoning evidence indicating a link among oxidative stress, membrane defects, immune dysfunction, and multineurotransmitter pathologies in SZ. Finally, the body of evidence reviewed herein provides a theoretical rationale for the development of novel treatment approaches.

Zhang, Y., Behrens, M. M., & Lisman, J. E. ( 2008).

Prolonged exposure to NMDAR antagonist suppresses inhibitory synaptic transmission in prefrontal cortex

Journal of Neurophysiology, 100( 2), 959-965.

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Zhang, Z.J., & Reynolds, G.P . ( 2002).

A selective decrease in the relative density of parvalbumin-immunoreactive neurons in the hippocampus in schizophrenia

Schizophrenia research, 55( 1-2), 1-10.

DOI:10.1016/S0920-9964(01)00188-8      URL     [本文引用: 3]

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