Parvalbumin陽性中間神經(jīng)元缺陷在精神分裂癥病理機制中的作用*

鄧瀟斐 郭建友

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Parvalbumin陽性中間神經(jīng)元缺陷在精神分裂癥病理機制中的作用*

鄧瀟斐1, 2郭建友1

(1中國科學院心理研究所 心理健康院重點實驗室, 北京 100101) (2中國科學院大學, 北京 100049)

精神分裂癥是一種多發(fā)于青壯年的重性精神病, 其原因尚不明確。經(jīng)典的多巴胺缺陷理論假說在某些方面欠缺解釋力; 與此同時, 關于Parvalbumin陽性的中間神經(jīng)元(后簡稱PV+神經(jīng)元)缺陷在精神分裂癥病理機制中的作用逐漸明晰, 并引起了越來越多的關注。PV+神經(jīng)元在絕大部分腦區(qū)中是一種快速放電的抑制性神經(jīng)元, 參與了突觸可塑性的調節(jié), 興奮/抑制平衡的維持和神經(jīng)發(fā)生等。而在精神分裂癥中, PV+神經(jīng)元的異常在患者和動物研究中都被普遍證實, 并發(fā)現(xiàn)與 NMDA受體缺陷、gamma波異常和氧化應激存在某些關聯(lián)。

精神分裂癥; 中間神經(jīng)元; NMDA受體; 氧化應激

1 前言

精神分裂癥是一種重性精神病, 多在青壯年時期發(fā)作, 是世界上十大致殘或使人喪失勞動能力的疾病之一, 同時也是各種精神疾病中患病率最高的一種, 其臨床表現(xiàn)癥狀各異, 涉及感知覺、思維、情感和行為等多方面的障礙以及精神活動的不協(xié)調, 包括幻想、妄想、偏執(zhí)和/或精神錯亂等陽性癥狀, 以及持續(xù)的進行性的感情淡漠、注意力不集中、社交回避、認知缺損等陰性癥狀。

目前精神分裂癥產(chǎn)生的病因并不十分明確, 科學家們通過臨床用藥經(jīng)驗和各種實驗證據(jù)來探索精神分裂癥產(chǎn)生的原因, 進而提出各種假說, 主要包括：多巴胺系統(tǒng)功能亢進假說(Davis & Kahn, 1991;Howes & Kapur, 2009)、γ-氨基丁酸(GABA)系統(tǒng)缺陷導致的興奮/抑制不平衡假說(Lewis, Hashimoto, & Volk, 2005)、NMDA (N-methyl-D- aspartic acid)受體缺陷假說(Jentsch & Roth, 1999; Tsai & Coyle, 2002)以及5-羥色胺(5-HT)受體異常假說等等(Breier, 1995; Abi-Dargham, Laruelle, Aghajanian, Charney, & Krystal, 1997)。其中, 多巴胺假說基于經(jīng)典的多巴胺受體拮抗類藥物對精神分裂癥治療有效的觀察而提出, 并獲得了大量實驗數(shù)據(jù)的支持, 因而成為精神分裂癥病理原因最經(jīng)典的解釋。但必須指出, 解剖學研究中并沒有發(fā)現(xiàn)多巴胺系統(tǒng)相關腦區(qū)和受體的病變, 提示多巴胺系統(tǒng)本身可能并非誘發(fā)精神分裂癥的根本原因(Gothelf et al., 2000)。

近年來, 精神分裂癥研究領域的另一個假說——大腦GABA系統(tǒng)缺陷假說逐漸引起了領域內研究者們的注意。其中, GABA能的小清蛋白陽性(parvalbumin positive, PV+)的中間神經(jīng)元獨特的性質和作用而備受關注(Cohen, Tsien, Goff, & Halassa, 2015)。PV+神經(jīng)元是一種快速放電的局部中間神經(jīng)元, 其能夠通過各種微環(huán)路構成的神經(jīng)網(wǎng)絡對同區(qū)域的錐體神經(jīng)元及其他中間神經(jīng)元進行調控(Hu, Gan, & Jonas, 2014; Tremblay, Lee, & Rudy, 2016), 還有證據(jù)表明, PV+神經(jīng)元參與了突觸可塑性(Caillard et al,. 2000; Donato, Rompani, & Caroni, 2013), 并在腦發(fā)育(尤其在視覺發(fā)育)關鍵期發(fā)揮了重要作用(Fagiolini et al., 2004; Katagiri, Fagiolini, & Hensch, 2007; Kuhlman et al., 2013; He et al., 2014; Gu et al., 2016)。近期許多研究表明, PV+神經(jīng)元在精神分裂癥中扮演了重要角色(Cohen et al., 2015; Steullet et al., 2017)。本文綜述了目前PV+神經(jīng)元對精神分裂癥影響的相關研究, 以期對了解該疾病的內在機制并開展進一步的研究提供借鑒。

2 PV+神經(jīng)元的介紹

若以還原論的視角盡可能簡單地描述大腦神經(jīng)網(wǎng)絡, 其主要由兩種類型的神經(jīng)元組成：提供興奮性神經(jīng)沖動的谷氨酸能主神經(jīng)元(Glutamate principal neurons)和擁有抑制功能的γ-氨基丁酸能中間神經(jīng)元(GABAergic interneurons)?？v觀全腦, 雖然GABA能中間神經(jīng)元僅占神經(jīng)元總量的10%~20% (Freund & Buzsáki, 1996; Aika, Ren, Kosaka & Kosaka, 1994; Halasy & Somogyi, 1993), 但由于其多樣化的形態(tài)結構與生理功能, 因而在調節(jié)、整合神經(jīng)網(wǎng)絡信號中發(fā)揮了極其重要的作用。此外, GABA能中間神經(jīng)元的功能受損也是導致各種遺傳發(fā)育及精神類疾病的主要原因(Marín, 2012)。

90年代以來, 很多實驗室開始研究一類特定的中間神經(jīng)元：快速放電的小清蛋白陽性表達中間神經(jīng)元(the fast-spiking parvalbumin-positive interneuron)。小清蛋白作為具有保守結構的酸性蛋白超家族的一員, 是一種小分子量(一般為9~ 11 kDa)的鈣離子綁定蛋白(Calcium binding protein, CaBP)。PV中間神經(jīng)元可根據(jù)其形態(tài)分為多種亞型, 并分別與錐體神經(jīng)元的特定部位形成突觸。其中最常見的是籃狀細胞(Basket cell)和吊燈狀細胞(Chandelier cell), 前者約占PV中間神經(jīng)元總量的90%, 主要投射到錐體神經(jīng)元的胞體和近端樹突; 后者則只與錐體神經(jīng)元的軸突起始部位形成突觸。由于PV+神經(jīng)元的軸突所靶向的細胞結構是錐體細神經(jīng)元對輸入信息作出反應并發(fā)放動作電位的關鍵部位, 因此PV+神經(jīng)元對錐體神經(jīng)元能否產(chǎn)生動作電位以及動作電位發(fā)放的時相起著重要的調控作用。

一般來說, PV陽性神經(jīng)元通常是GABA能的。Celio和Heizmann (1981)通過免疫熒光雙標GAD (一種GABA能神經(jīng)元的免疫標記物)和PV, 證實PV陽性的神經(jīng)元分布和GABA能神經(jīng)元的分布有很高的一致性, 在大腦皮層中, 幾乎所有的PV+神經(jīng)元都是GABA能的, 同時, 70-80%的GABA能神經(jīng)元含有PV。在海馬的CA1區(qū), 11%的神經(jīng)元是GABA能的, 而這些GABA能神經(jīng)元中24%是PV+神經(jīng)元(Bezaire & Soltesz, 2013)。然而近年來有越來越多的證據(jù)表明, 谷氨酸能的PV陽性神經(jīng)元不僅存在, 而且在神經(jīng)系統(tǒng)中扮演了重要角色。例如, 最近有研究證明上丘中表達的PV的興奮性投射神經(jīng)元是參與激發(fā)“戰(zhàn)斗?逃跑”反應的關鍵神經(jīng)元亞型(Shang et al, 2015)。

20年前, 這種中間神經(jīng)元的性質完全不為人知。20年后, 受益于膜片鉗、同步多細胞記錄、光遺傳、鈣離子成像等等技術的廣泛使用, 我們對PV中間神經(jīng)元的認識變得比其他幾種中間神經(jīng)元要更多。它們不僅參與了基礎的微環(huán)路功能, 例如前饋抑制和反饋抑制(Buzsàki & Eidelberg, 1981; Miles,1990; Pouille & Scanziani, 2001, 2004), 或gamma震蕩波的產(chǎn)生(Bartos, Vida & Jonas, 2007; Cardin et al, 2009; Sohal, Zhang, Yizhar, & Deisseroth, 2009; Stark et al, 2013); 還參與了復雜的神經(jīng)網(wǎng)絡運作, 例如大腦發(fā)育“關鍵期”突觸可塑性的調控(He et al., 2014)以及感知反應的增益調節(jié)(Hu et al., 2014)等等。此外, PV+神經(jīng)元也在多種腦疾病中扮演重要角色(例如癲癇、自閉癥、精神分裂癥), 因此也是很多臨床腦疾病的未來的治療的潛在方向。

3 PV+中間神經(jīng)元與精神分裂癥

3.1 與精神分裂癥相關的PV+中間神經(jīng)元變化

精神分裂癥最顯著表現(xiàn)就是前額葉(Lewis et al., 2005)和海馬(Zhang & Reynolds, 2002)的GABA系統(tǒng)的改變。具體表征有GAD67表達和PV+神經(jīng)元數(shù)量減少(Todtenkopf & Benes, 1998; Hashimoto et al., 2003)。例如, 在精神分裂癥患者的尸檢研究, 發(fā)現(xiàn)了幾個腦區(qū)中PV+神經(jīng)元選擇性地減少, 包括內側前額葉(medial prefrontal cortex, mPFC)、丘腦、內嗅皮層(entorhinal cortex)和海馬前部(Beasley & Reynolds, 1997; Bitanihirwe, Lim, Kelley, Kaneko, & Woo, 2009; Pantazopoulos, Woo, Lim, Lange, & Berretta, 2007; Zhang & Reynolds, 2002)。其中以海馬的相關報道最為常見, Zhang和Reynolds (2002)甚至在精神分裂癥患者海馬的所有亞區(qū)都發(fā)現(xiàn)了PV中間神經(jīng)元密度的降低, 而作為對照的另一種GABA能的中間神經(jīng)元—— Calretinin+神經(jīng)元的密度則不受影響。近年來, 很多證據(jù)都將海馬定位為精神分裂癥發(fā)病的中樞, 甚至是始發(fā)腦區(qū), 其他腦區(qū)的變化可能只是海馬病變的次級效應。該理論認為, 海馬前部GABA能中間神經(jīng)元(主要是PV+神經(jīng)元)的功能失調極大地削弱了對該腦區(qū)的抑制控制, 興奮/抑制的平衡被打破, 從而導致其活動水平異常增強(Behrens & Sejnowski, 2009; Lodge, Behrens, & Grace, 2009; Grace, 2012)。例如, 對精分患者的功能性成像揭示了其海馬的過度激活(Malaspina et al., 1999; Medoff, Holcomb, Lahti & Tamminga, 2001; Heckers, 2004; Schobel et al., 2009; Kraguljac, White, Reid & Lahti, 2013)。

PV缺陷在精神分裂癥的動物模型中也得到了印證。例如, 在精神分裂癥的MAM模型中, 在母鼠懷孕第15天腹腔注射神經(jīng)毒素甲基氧化偶氮甲醇(methylazoxymethanol, MAM)誘發(fā)子代出現(xiàn)精神分裂樣癥狀, 發(fā)現(xiàn)MAM注射會導致成年后的子代腹側海馬的的PV+神經(jīng)元特異性地喪失(Lodge et al., 2009)。此外, 在精神分裂癥的polyribocytidilic (polyIC)模型(給懷孕17天的孕鼠注射polyIC)中, 也出現(xiàn)了mPFC和vHPC的PV+神經(jīng)元減少的現(xiàn)象以及安非他明誘發(fā)的運動增強(Meyer, Nyffeler, Yee, Knuesel & Feldon, 2008)。

此外, 包括精神分裂癥在內的許多精神疾病還伴隨著異常的神經(jīng)發(fā)生(neurogenesis), 由于抑制性神經(jīng)遞質GABA在神經(jīng)發(fā)生的各個階段均發(fā)揮著重要的作用, 包括PV+神經(jīng)元在內的GABA能中間神經(jīng)元的缺陷很有可能是導致此類疾病中神經(jīng)發(fā)生異常的原因。有文獻報道在海馬的齒狀回顆粒細胞下層(subgranular zone,SGZ)的PV+神經(jīng)元能夠調控新生神經(jīng)元的分裂成熟、樹突的發(fā)育及突觸整合(Ge et al., 2006; Song et al., 2013)。Song等人(2013)利用光遺傳技術發(fā)現(xiàn)PV+神經(jīng)元特異地對I型細胞的增殖和自我更新具有調控作用。此外, PV+神經(jīng)元還能影響新生神經(jīng)元的存活, Wang等(2014)發(fā)現(xiàn)敲除PV陽性中間神經(jīng)元的淀粉樣前體蛋白(amyloid precursor protein, APP)可以影響突觸周圍GABA的含量, 進而減少海馬齒狀回區(qū)新生顆粒細胞(DGCs)的存活。

因此, PV+神經(jīng)元功能功能的健全與否關系到中樞神經(jīng)系統(tǒng)的興奮/抑制平衡的維持和神經(jīng)發(fā)生的正常進行, 因而成為包括精神分裂癥在內的眾多精神病領域的熱門研究對象(Kobayashi & Buckmaster, 2003; Gogolla et al., 2009; Burguière, Monteiro, Feng & Graybiel, 2013; Steullet et al., 2017)。下文將以精神分裂癥中PV+神經(jīng)元的異變?yōu)殄^點, 結合精分研究領域中最常見的三種病理表征(NMDA受體缺陷、gamma波異常和氧化應激),進一步介紹PV+神經(jīng)元在精神分裂癥中的作用。

3.2 精神分裂癥的gamma波異常與PV+神經(jīng)元缺陷

Gamma波缺陷常見于精神分裂癥的相關研究中, 是其重要的癥狀表型之一。在對精神分裂癥患者的研究中, Gamma波異常的具體表現(xiàn)形式呈現(xiàn)多樣性, 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), 以及特定頻段的gamma波減少(Spencer et al., 2003; Spencer, Niznikiewicz, Shenton, & McCarley, 2008; Uhlhaas et al., 2006)等等, 考慮到上述研究都是事件相關的, 出現(xiàn)這種多樣性可能是所采用的認知任務本身的不同所導致的(Hunt, Kopell, Traub, & Whittington, 2017)。同樣的, 精神分裂的易感基因模型也表現(xiàn)出gamma波缺陷, 比如Neuregulin, erbB4和calcineurin等基因的突變在誘發(fā)小鼠精分樣行為的同時, 伴隨了gamma波的增加(Del Pino et al., 2013; Fisahn, Neddens, Yan, & Buonanno, 2008; Suh, Foster, Davoudi, Wilson, & Tonegawa, 2013)。

由于Gamma神經(jīng)振蕩的產(chǎn)生需要對主神經(jīng)元產(chǎn)生強烈的協(xié)同性抑制(Gonzalez-Burgos & Lewis, 2008), 精神分裂中常見的GABA神經(jīng)傳遞的缺陷被認為是導致gamma異常的潛在機制(Lewis, Curley, Glausier, & Volk, 2012); 鑒于PV+神經(jīng)元是gamma蕩波形成的關鍵因素(Bartos et al, 2007; Cardin et al, 2009; Stark et al, 2013), 且又是在精神分裂癥中突觸傳遞功能受損最嚴重(熒光原位雜交中檢測到丟失GAD67 mRNA最多)的GABA能中間神經(jīng)元亞型(Hashimoto et al., 2003), 提示二者在精神分裂癥中存在緊密的聯(lián)系, 并得到了相關實驗證據(jù)的支持——在精神分裂癥的動物研究中, 就多次觀察到PV表達和gamma波的同步減少(Cunningham et al., 2006; Lodge et al, 2009; Steullet et al., 2010)。因而大量的研究者認為, 精神分裂癥中常見的PV+神經(jīng)元受損或許能為該疾病狀態(tài)下執(zhí)行認知任務時不正常的gamma波提供合理的解釋(Lewis et al., 2012; Volk, Gonzalez- Burgos, & Lewis, 2016; Uhlhaas & Singer, 2010)。譬如說, Kim, ?hrlund-Richter, Wang, Deisseroth和Carlén(2016)揭示了內側前額葉的PV+神經(jīng)元介導的gamma波是產(chǎn)生自上而下注意的關鍵因素, 可能是包括精神分裂癥在內的多種精神疾病中廣泛存在的注意力缺陷的內在病理機制。值得注意的是, 前文提到PV+神經(jīng)元可根據(jù)結構分為兩種亞型, 有研究者認為是PV+神經(jīng)元的籃狀細胞, 而不是吊燈狀細胞的突觸前或突觸后的變化導致了精神分裂中的gamma波的紊亂和認知損傷(Lewis et al., 2012; Gonzalez-Burgos & Lewis, 2012), 但由于目前尚無法在細胞層面對這兩種PV+神經(jīng)元亞型進行分別的操縱, 因此還沒有最直接的證據(jù)。

3.3 精神分裂癥的NMDA受體缺陷與PV+神經(jīng)元缺陷

NMDA受體缺陷假說也是精神分裂癥的經(jīng)典假說之一, 自Luby等人(1959)發(fā)現(xiàn)NMDA受體拮抗劑PCP (phencycline)可以在正常人身上引發(fā)類似精神分裂癥樣的行為表征后, 該假說在精神分裂癥領域一直備受關注。在此之后, 包括PCP在內的很多NMDA受體拮抗劑(例如APV, CPP, MK-801和Ketamine)陸續(xù)被發(fā)現(xiàn)能夠引發(fā)精神分裂癥樣癥狀, 并被應用于精神分裂癥研究的動物造模中(Javitt & Zukin, 1991; Krystal et al., 1994; Olney & Farber, 1995)。

很多證據(jù)表明NMDA受體與PV+神經(jīng)元之間存在密切的關系。NMDA受體被發(fā)現(xiàn)能夠干預中樞神經(jīng)系統(tǒng)中GAD67和PV的表達(Kinney et al., 2006; Romón & Adell, 2011; Abekawa, Ito, Nakagawa, & Koyama, 2007), 影響PV+神經(jīng)元的抑制性突觸傳遞(Zhang, Behrens, & Lisman, 2008), 還可以調節(jié)其放電特性(Albéri, Lintas, Kretz, Schwaller, & Villa, 2013)與突觸可塑性(Caillard et al., 2000)。此外, 有證據(jù)表明NMDA受體的NR2A亞基在PV+神經(jīng)元中可能扮演重要角色, 通過單細胞分離mRNA測定不同類型細胞中NR2A/NR2B的比率, 發(fā)現(xiàn)PV+神經(jīng)元中NR2A/NR2B的mRNA表達量之比是錐體神經(jīng)元的五倍, 進一步的藥理實驗揭示了NR2A而不是NR2B的選擇性拮抗劑減少了PV的表達(Kinney et al., 2006)。

考慮到精神分裂癥中普遍報道的PV+神經(jīng)元缺陷, 上述研究暗示NMDA受體受損可能是導致精神分裂癥中PV+神經(jīng)元結構和功能異常的關鍵因素。換句話說, PV+神經(jīng)元受損在精神分裂癥中可能是NMDA受體功能失調的二級效應。NMDA受體功能不全導致PV+神經(jīng)元更難以被興奮, 由于PV+神經(jīng)元是重要的抑制性神經(jīng)元, 其在局部神經(jīng)微環(huán)路中角色的缺失會直接引起錐體神經(jīng)元的興奮性的增加, 使得神經(jīng)網(wǎng)絡去抑制, 從而導致大腦興奮/抑制水平的失衡, 進而引發(fā)精神疾病(Cohen et al., 2015; Lisman et al.,2008)。最直觀的證據(jù)來自轉基因動物的研究, 例如, Belforte等人(2010)發(fā)現(xiàn), 在敲除NMDA受體誘發(fā)出GAD67和PV表達下調的同時, 動物還表現(xiàn)出精神分裂癥樣的行為。而在PV+神經(jīng)元中特異性地敲除NR1亞基的基因(使得NMDA受體無法在PV+神經(jīng)元中表達), 會導致該轉基因動物表現(xiàn)出腦電波異常(Carlen et al., 2012; Korotkova, Fuchs, Ponomarenko, von Engelhardt, & Monyer, 2010; Billingslea et al., 2014; Gonzalez-Burgos & Lewis, 2012), 認知功能受損(Carlen et al., 2012; Korotkova et al., 2010), 社交障礙(Saunders et al., 2013; Billingslea et al., 2014)等精神分裂癥中常見的癥狀表現(xiàn)。

與此同時, 精神分裂癥中Gamma波的異常也間接佐證了上述推測。前文提到, PV+神經(jīng)元是參與Gamma波形成的必要條件(Sohal et al., 2009; Bartos et al., 2007; Cardin et al, 2009; Stark et al, 2013), 而gamma波異常又是精神分裂癥的常見表型(Bartos et al., 2007; Klausberger & Somogyi, 2008; Cardin et al., 2009; Lodge et al., 2009)。在此基礎上, 一些研究者采用藥理阻斷或者基因刪除的方式來操控PV+神經(jīng)元中的NMDR受體, 成功干擾了Gamma波(Lisman et al., 2008; Gonzalez- Burgos & Lewis, 2012; Korotkova et al., 2010; Carlen et al., 2012; Kocsis, 2012), 證明了PV+神經(jīng)元中的NMDR受體的確在gamma波的形成中起到重要作用, 其功能紊亂可能是精神分裂癥中gamma波異常的潛在病理原因之一。值得注意的是, 上述實驗結果可能存在發(fā)育階段的特異性：只表現(xiàn)在出生后早期刪除NMDA受體的動物身上, 而不能表現(xiàn)在青春期后刪除NMDA受體的動物上(Belforte et al., 2010); 這說明NMDA受體不僅參與協(xié)同局部微環(huán)路的神經(jīng)振蕩, 而且對PV+神經(jīng)元生理功能的發(fā)育成熟是必不可少的(Cohen et al., 2015)。

3.4 精神分裂癥氧化應激上調與PV+神經(jīng)元缺陷

氧化應激(oxidative stress), 指的是人體在異常狀態(tài)下, 氧化和抗氧化機制失衡, 導致過量的自由基對神經(jīng)元和大腦的損害作用, 它與神經(jīng)炎癥關聯(lián)緊密。而在精神分裂癥中, 大腦的氧化應激/氧化還原機能的紊亂已被多次證明, 并逐漸成為領域內的共識(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)利用磷磁共振波譜(Phosphorus magnetic resonance spectroscopy, P-MRS)進行NAD+/NADH的檢測, 首次在人類身上證明了精神分裂癥的抗氧化機能失調。大腦抗氧化機能的失調包括腦內谷胱甘肽(glutathione, GSH) 的減少(Do et al,2009), 由于GSH是主要的內源性抗氧化劑和氧化還原反應的調節(jié)劑, 其合成缺陷會導致小鼠腹側海馬的CA3和齒狀回的PV+神經(jīng)元選擇性地減少, 并伴隨著β/γ神經(jīng)震蕩的減少, 并引起相關的精神病樣行為癥狀(Steullet et al., 2010)。

精神分裂癥中的PV+神經(jīng)元損傷和過度的氧化應激之間存在重要聯(lián)系, 許多精分相關的環(huán)境風險因素/早期應激源能夠干擾抗氧化系統(tǒng), 增加氧化應激(Do et al., 2009)和神經(jīng)炎癥(Brenhouse &Andersen, 2011; Gárate et al., 2013; Kaur, Rathnasamy, & Ling., 2013), 并且減少前額葉和海馬的PV表達(Dell'Anna, Geloso, Magarelli & Molinari, 1996; Harte, Powell, Swerdlow, Geyer, & Reynolds, 2007; Meyer et al, 2008; Brenhouse & Andersen, 2011; Komitova et al., 2013)。雖然上述研究并沒有闡明二者之間的因果關系, 但種種跡象表明, 氧化應激是導致PV+神經(jīng)元損傷的重要原因。

首先, 在時間順序上, 氧化應激發(fā)生在PV+神經(jīng)元呈現(xiàn)缺陷之前(Steullet et al., 2010); 其次, 在多種精神分裂的動物模型中都證實了, 抗氧化應激藥物對PV+神經(jīng)元的起到了有效的保護作用(Cabungcal, Steullet, Kraftsik, Cuenod & Do, 2013; Behrens et al., 2007; Schiavone et al., 2009; Cabungcal et al., 2014; Jiang, Rompala, Zhang, Cowell, & Nakazawa, 2013)。為了進一步驗證氧化應激誘發(fā)的PV+神經(jīng)元缺陷是否是精神分裂癥的普適性病理原因, 最近Steullet等人(2017)在多達9種精神分裂癥模型動物(大體可分為基因模型、損毀模型、藥理模型和環(huán)境模型)的前扣帶回(ACC)中免疫共染了PV、PNN (環(huán)神經(jīng)元周圍網(wǎng), Perineuronal nets)和8-oxo-dG (氧化應激的標記物), 結果發(fā)現(xiàn), 除了兩種模型動物沒有表現(xiàn)出以上三種標記物的任何改變, 在其余的動物中, PV+神經(jīng)元缺陷必然伴隨著不同程度的氧化應激。綜上, 我們可以得出結論, 由過度的氧化應激引發(fā)的PV+神經(jīng)元缺陷在精神分裂癥中是一個普遍現(xiàn)象, 它可能是該疾病的大多數(shù)易感因素(包括藥物、環(huán)境、基因等)最終誘發(fā)精分表型的“必經(jīng)之路”。

然而, 上述結論引申出了另一個重要的問題：過度的氧化應激是如何選擇性地損傷PV+神經(jīng)元, 而不是其他神經(jīng)細胞呢？精神分裂癥中可普遍觀察到的PNN的異常變化為我們提供了參考答案(Steullet et al., 2017; Mauney et al., 2013; Pantazopoulos, Woo, Lim, Lange, & Berretta, 2010)。PNN是一種具有細胞特異性的胞外基質(extracellular matrix)結構, 它主要包裹在PV+神經(jīng)元的胞體和近端神經(jīng)突(Rossier et al., 2015)。有證據(jù)表明PNN是保護PV+神經(jīng)元不受氧化應激損傷的重要結構(Cabungcal et al., 2013), 因此精神分裂癥中的PV+神經(jīng)元缺陷可能是由于PNN異常導致PV 神經(jīng)元失去對氧化應激的防御機制所引發(fā)的次級效應(Cohen et al., 2015)。

4 總結和展望

盡管精神分裂癥已經(jīng)被研究多年, 相關假設和實驗結果層出不窮, 然而我們對其病理機制仍然不是很清楚。在其中, PV+神經(jīng)元缺陷只是該疾病眾多神經(jīng)生理變化的其中一隅, 然而近年來的種種實驗證據(jù)都最終指向了PV+神經(jīng)元異常, 提示PV+神經(jīng)元在該疾病中可能扮演重要角色。因此, 本文立足于PV+神經(jīng)元的基本結構功能及其在精神分裂癥中的缺陷, 對其在精神分裂癥中的改變及其相關的實驗證據(jù)進行了綜述, 以期為相關研究的深入探索提供借鑒和支持。

包括PV+神經(jīng)元在內的中間神經(jīng)元之間存在著復雜而重要的相互作用, 它們和主神經(jīng)元一起構建了精細的神經(jīng)微環(huán)路系統(tǒng), 共同決定了大腦認知功能的正常運行(Wolff et al., 2014; Markram et al., 2004)。在其中, PV+神經(jīng)元是被研究得最多的一種GABA能中間神經(jīng)元, 這一方面是因為它是皮層中最多的中間神經(jīng)元(占中間神經(jīng)元總數(shù)的40%) (Tremblay et al., 2016), 另一方面則是因為其快速高頻放電的特性而在電生理記錄中更具有區(qū)分度。而在精神分裂癥中, PV+神經(jīng)元也比其他中間神經(jīng)元受到了更多的關注, 這種偏愛的理由其實依然基于上述兩個方面, 這種慣性使得大多數(shù)精神分裂癥研究中所指出的PV缺陷的結果缺乏特異性。盡管有充足的證據(jù)表明, 精神病患者的大腦表現(xiàn)出PV、SOM和CCK表達的同步下調, 暗示了多種中間神經(jīng)元亞型在該疾病中的參與(Morris, Hashimoto & Lewis, 2008; Konradi et al., 2011), 但我們仍然不清楚其它中間神經(jīng)元(比如SOM+神經(jīng)元, VIP+神經(jīng)元)是如何參與了精神分裂癥, 是否也和gamma缺陷, NMDA受體異常和氧化應激, 以及其它認知和生理上的病變存在某種聯(lián)系。鑒于以上原因, 未來的研究應試圖闡明不同的中間神經(jīng)元亞群在精神分裂癥中的潛在機制和作用權重。

與此同時, 圍繞PV+神經(jīng)元突觸前后相關受體為靶點進行的抗精神病藥物的開發(fā)也在進行中, 目前的關注點主要集中在GABAA受體上, 尤其是α1-6亞基(Gill & Grace, 2014)。在新皮層和海馬中, 含α5亞基的 GABAA受體位于PV+神經(jīng)元突觸后, 影響PV+神經(jīng)元對錐體神經(jīng)元的調控; 而含α1和α2/3 亞基的 GABAA受體則主要分布于PV+神經(jīng)元突觸前, 接收來自其他神經(jīng)元的抑制性信號(Ali & Thomson, 2007)。其中又以GABAA受體5α亞基最為矚目, 已有藥理實驗表明5α GABAA受體激動劑能在一定程度上扭轉精神分裂癥相關的認知缺陷(Featherstone, Rizos, Nobrega, Kapur, & Fletcher, 2007;Gill, Lodge, Cook, Aras, & Grace, 2011; Gill & Grace, 2014)。盡管如此, 目前尚未有此類藥物通過臨床實驗的報道, 但這仍不失為新的抗精神病藥物開發(fā)的一個方向。

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Roles of impaired parvalbumin positive interneurons in schizophrenic pathology

DENG Xiaofei1,2; GUO Jianyou1

(1Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, China)(2University of Chinese Academy of Sciences, Beijing 100049, China)

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.

schizophrenia; interneurons; NMDA receptors; oxidative stress.

10.3724/SP.J.1042.2018.01992

2017-12-04

*國家自然科學基金(30800301, 31170992, 31371038) 資助。

郭建友, E-mail: guojy@psych.ac.cn

B845