Parvalbumin陽性中間神經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于青壯年的重性精神病, 其原因尚不明確。經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陽性的中間神經元(后簡稱PV+神經元)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+神經元在絕大部分腦區中是一種快速放電的抑制性神經元, 參與了突觸可塑性的調節, 興奮/抑制平衡的維持和神經發生等。而在精神分裂癥中, PV+神經元的異常在患者和動物研究中都被普遍證實, 并發現與 NMDA受體缺陷、gamma波異常和氧化應激存在某些關聯。

精神分裂癥; 中間神經元; 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調, 包括幻想、妄想、偏執和/或精神錯亂等陽性癥狀, 以及持續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。

目前精神分裂癥產生的病因并不十分明確, 科學家們通過臨床用藥經驗和各種實驗證據來探索精神分裂癥產生的原因, 進而提出各種假說, 主要包括：多巴胺系統功能亢進假說(Davis & Kahn, 1991;Howes & Kapur, 2009)、γ-氨基丁酸(GABA)系統缺陷導致的興奮/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據的支持, 因而成為精神分裂癥病理原因最經典的解釋。但必須指出, 解剖學研究中并沒有發現多巴胺系統相關腦區和受體的病變, 提示多巴胺系統本身可能并非誘發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+)的中間神經元獨特的性質和作用而備受關注(Cohen, Tsien, Goff, & Halassa, 2015)。PV+神經元是一種快速放電的局部中間神經元, 其能夠通過各種微環路構成的神經網絡對同區域的錐體神經元及其他中間神經元進行調控(Hu, Gan, & Jonas, 2014; Tremblay, Lee, & Rudy, 2016), 還有證據表明, PV+神經元參與了突觸可塑性(Caillard et al,. 2000; Donato, Rompani, & Caroni, 2013), 并在腦發育(尤其在視覺發育)關鍵期發揮了重要作用(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+神經元的介紹

若以還原論的視角盡可能簡單地描述大腦神經網絡, 其主要由兩種類型的神經元組成：提供興奮性神經沖動的谷氨酸能主神經元(Glutamate principal neurons)和擁有抑制功能的γ-氨基丁酸能中間神經元(GABAergic interneurons)。縱觀全腦, 雖然GABA能中間神經元僅占神經元總量的10%~20% (Freund & Buzsáki, 1996; Aika, Ren, Kosaka & Kosaka, 1994; Halasy & Somogyi, 1993), 但由于其多樣化的形態結構與生理功能, 因而在調節、整合神經網絡信號中發揮了極其重要的作用。此外, GABA能中間神經元的功能受損也是導致各種遺傳發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元：快速放電的小清蛋白陽性表達中間神經元(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中間神經元可根據其形態分為多種亞型, 并分別與錐體神經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中間神經元總量的90%, 主要投射到錐體神經元的胞體和近端樹突; 后者則只與錐體神經元的軸突起始部位形成突觸。由于PV+神經元的軸突所靶向的細胞結構是錐體細神經元對輸入信息作出反應并發放動作電位的關鍵部位, 因此PV+神經元對錐體神經元能否產生動作電位以及動作電位發放的時相起著重要的調控作用。

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

20年前, 這種中間神經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中間神經元的認識變得比其他幾種中間神經元要更多。它們不僅參與了基礎的微環路功能, 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網絡運作, 例如大腦發育“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(Hu et al., 2014)等等。此外, PV+神經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+中間神經元與精神分裂癥

3.1 與精神分裂癥相關的PV+中間神經元變化

精神分裂癥最顯著表現就是前額葉(Lewis et al., 2005)和海馬(Zhang & Reynolds, 2002)的GABA系統的改變。具體表征有GAD67表達和PV+神經元數量減少(Todtenkopf & Benes, 1998; Hashimoto et al., 2003)。例如, 在精神分裂癥患者的尸檢研究, 發現了幾個腦區中PV+神經元選擇性地減少, 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都發現了PV中間神經元密度的降低, 而作為對照的另一種GABA能的中間神經元—— Calretinin+神經元的密度則不受影響。近年來, 很多證據都將海馬定位為精神分裂癥發病的中樞, 甚至是始發腦區, 其他腦區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能中間神經元(主要是PV+神經元)的功能失調極大地削弱了對該腦區的抑制控制, 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天腹腔注射神經毒素甲基氧化偶氮甲醇(methylazoxymethanol, MAM)誘發子代出現精神分裂樣癥狀, 發現MAM注射會導致成年后的子代腹側海馬的的PV+神經元特異性地喪失(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, 也出現了mPFC和vHPC的PV+神經元減少的現象以及安非他明誘發的運動增強(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發生(neurogenesis), 由于抑制性神經遞質GABA在神經發生的各個階段均發揮著重要的作用, 包括PV+神經元在內的GABA能中間神經元的缺陷很有可能是導致此類疾病中神經發生異常的原因。有文獻報道在海馬的齒狀回顆粒細胞下層(subgranular zone,SGZ)的PV+神經元能夠調控新生神經元的分裂成熟、樹突的發育及突觸整合(Ge et al., 2006; Song et al., 2013)。Song等人(2013)利用光遺傳技術發現PV+神經元特異地對I型細胞的增殖和自我更新具有調控作用。此外, PV+神經元還能影響新生神經元的存活, Wang等(2014)發現敲除PV陽性中間神經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新生顆粒細胞(DGCs)的存活。

因此, PV+神經元功能功能的健全與否關系到中樞神經系統的興奮/抑制平衡的維持和神經發生的正常進行, 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+神經元的異變為錨點, 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波異常的具體表現形式呈現多樣性, 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出gamma波缺陷, 比如Neuregulin, erbB4和calcineurin等基因的突變在誘發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神經振蕩的產生需要對主神經元產生強烈的協同性抑制(Gonzalez-Burgos & Lewis, 2008), 精神分裂中常見的GABA神經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能中間神經元亞型(Hashimoto et al., 2003), 提示二者在精神分裂癥中存在緊密的聯系, 并得到了相關實驗證據的支持——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+神經元受損或許能為該疾病狀態下執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+神經元介導的gamma波是產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+神經元可根據結構分為兩種亞型, 有研究者認為是PV+神經元的籃狀細胞, 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+神經元亞型進行分別的操縱, 因此還沒有最直接的證據。

3.3 精神分裂癥的NMDA受體缺陷與PV+神經元缺陷

NMDA受體缺陷假說也是精神分裂癥的經典假說之一, 自Luby等人(1959)發現NMDA受體拮抗劑PCP (phencycline)可以在正常人身上引發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)陸續被發現能夠引發精神分裂癥樣癥狀, 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)。

很多證據表明NMDA受體與PV+神經元之間存在密切的關系。NMDA受體被發現能夠干預中樞神經系統中GAD67和PV的表達(Kinney et al., 2006; Romón & Adell, 2011; Abekawa, Ito, Nakagawa, & Koyama, 2007), 影響PV+神經元的抑制性突觸傳遞(Zhang, Behrens, & Lisman, 2008), 還可以調節其放電特性(Albéri, Lintas, Kretz, Schwaller, & Villa, 2013)與突觸可塑性(Caillard et al., 2000)。此外, 有證據表明NMDA受體的NR2A亞基在PV+神經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, 發現PV+神經元中NR2A/NR2B的mRNA表達量之比是錐體神經元的五倍, 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+神經元結構和功能異常的關鍵因素。換句話說, PV+神經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+神經元更難以被興奮, 由于PV+神經元是重要的抑制性神經元, 其在局部神經微環路中角色的缺失會直接引起錐體神經元的興奮性的增加, 使得神經網絡去抑制, 從而導致大腦興奮/抑制水平的失衡, 進而引發精神疾病(Cohen et al., 2015; Lisman et al.,2008)。最直觀的證據來自轉基因動物的研究, 例如, Belforte等人(2010)發現, 在敲除NMDA受體誘發出GAD67和PV表達下調的同時, 動物還表現出精神分裂癥樣的行為。而在PV+神經元中特異性地敲除NR1亞基的基因(使得NMDA受體無法在PV+神經元中表達), 會導致該轉基因動物表現出腦電波異常(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。

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育階段的特異性：只表現在出生后早期刪除NMDA受體的動物身上, 而不能表現在青春期后刪除NMDA受體的動物上(Belforte et al., 2010); 這說明NMDA受體不僅參與協同局部微環路的神經振蕩, 而且對PV+神經元生理功能的發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+神經元缺陷

氧化應激(oxidative stress), 指的是人體在異常狀態下, 氧化和抗氧化機制失衡, 導致過量的自由基對神經元和大腦的損害作用, 它與神經炎癥關聯緊密。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+神經元選擇性地減少, 并伴隨著β/γ神經震蕩的減少, 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+神經元損傷和過度的氧化應激之間存在重要聯系, 許多精分相關的環境風險因素/早期應激源能夠干擾抗氧化系統, 增加氧化應激(Do et al., 2009)和神經炎癥(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+神經元損傷的重要原因。

首先, 在時間順序上, 氧化應激發生在PV+神經元呈現缺陷之前(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的PV+神經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、藥理模型和環境模型)的前扣帶回(ACC)中免疫共染了PV、PNN (環神經元周圍網, Perineuronal nets)和8-oxo-dG (氧化應激的標記物), 結果發現, 除了兩種模型動物沒有表現出以上三種標記物的任何改變, 在其余的動物中, PV+神經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的PV+神經元缺陷在精神分裂癥中是一個普遍現象, 它可能是該疾病的大多數易感因素(包括藥物、環境、基因等)最終誘發精分表型的“必經之路”。

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+神經元, 而不是其他神經細胞呢？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+神經元的胞體和近端神經突(Rossier et al., 2015)。有證據表明PNN是保護PV+神經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+神經元缺陷可能是由于PNN異常導致PV 神經元失去對氧化應激的防御機制所引發的次級效應(Cohen et al., 2015)。

4 總結和展望

盡管精神分裂癥已經被研究多年, 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+神經元缺陷只是該疾病眾多神經生理變化的其中一隅, 然而近年來的種種實驗證據都最終指向了PV+神經元異常, 提示PV+神經元在該疾病中可能扮演重要角色。因此, 本文立足于PV+神經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+神經元在內的中間神經元之間存在著復雜而重要的相互作用, 它們和主神經元一起構建了精細的神經微環路系統, 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+神經元是被研究得最多的一種GABA能中間神經元, 這一方面是因為它是皮層中最多的中間神經元(占中間神經元總數的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分度。而在精神分裂癥中, PV+神經元也比其他中間神經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。盡管有充足的證據表明, 精神病患者的大腦表現出PV、SOM和CCK表達的同步下調, 暗示了多種中間神經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元(比如SOM+神經元, VIP+神經元)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系。鑒于以上原因, 未來的研究應試圖闡明不同的中間神經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+神經元突觸前后相關受體為靶點進行的抗精神病藥物的開發也在進行中, 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+神經元突觸后, 影響PV+神經元對錐體神經元的調控; 而含α1和α2/3 亞基的 GABAA受體則主要分布于PV+神經元突觸前, 接收來自其他神經元的抑制性信號(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的一個方向。

Abekawa, T., Ito, K., Nakagawa, S., & Koyama, T. (2007). Prenatal exposure to an NMDA receptor antagonist, MK-801 reduces density of parvalbumin-immunoreactive GABAergic neurons in the medial prefrontal cortex and enhances phencyclidine-induced hyperlocomotion but not behavioral sensitization to methamphetamine in postpubertal rats.(3), 303?316.

Abi-Dargham, A., Laruelle, M., Aghajanian, G. K., Charney, D., & Krystal, J. (1997). The role of serotonin in the pathophysiology and treatment of schizophrenia.(1), 1?17.

Aika, Y., Ren, J. Q., Kosaka, K., & Kosaka, T. (1994). Quantitative analysis of GABA-like-immunoreactive and parvalbumin-containing neurons in the CA1 region of the rat hippocampus using a stereological method, the disector.(2), 267?276.

Albéri, L., Lintas, A., Kretz, R., Schwaller, B., & Villa, A. E. P. (2013). The calcium-binding protein parvalbumin modulates the firing 1 properties of the reticular thalamic nucleus bursting neurons.(11), 2827?2841.

Ali, A. B., & Thomson, A. M. (2007). Synaptic α5 subunit– containing GABAA receptors mediate IPSPs elicited by dendrite-preferring cells in rat neocortex.(6), 1260?1271.

Barr, M. S., Farzan, F., Tran, L. C., Chen, R., Fitzgerald, P. B., & Daskalakis, Z. J. (2010). Evidence for excessive frontal evoked gamma oscillatory activity in schizophrenia during working memory.(1-3), 146?152.

Bartos, M., Vida, I., & Jonas, P. (2007). Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks.(1), 45?56.

Beasley, C. L., & Reynolds, G. P. (1997). Parvalbumin- immunoreactive neurons are reduced in the prefrontal cortex of schizophrenics.(3), 349?355.

Belforte, J. E., Zsiros, V., Sklar, E. R., Jiang, Z., Yu, G., Li, Y., ... Nakazawa, K. (2010). Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia- like phenotypes.(1), 76?83.

Behrens, M. M., Ali, S. S., Dao, D. N., Lucero, J., Shekhtman, G., Quick, K. L., & Dugan, L. L. (2007). Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase.(5856), 1645?1647.

Behrens, M. M., & Sejnowski, T. J. (2009). Does schizophreniaarise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex?.(3), 193?200.

Bezaire, M. J., & Soltesz, I. (2013). Quantitative assessment of CA1 local circuits: Knowledge base for interneuron‐ pyramidal cell connectivity.(9), 751?785.

Billingslea, E. N., Tatard-Leitman, V. M., Anguiano, J., Jutzeler, C. R., Suh, J., Saunders, J. A., ... Siegel, S. J. (2014). Parvalbumin cell ablation of NMDA-R1 causes increased resting network excitability with associated social and self-care deficits.(7), 1603?1613.

Bitanihirwe, B. K. Y., Lim, M. P., Kelley, J. F., Kaneko, T., & Woo, T. (2009). Glutamatergic deficits and parvalbumin- containing inhibitory neurons in the prefrontal cortex in schizophrenia.(71), 1.

Breier, A. (1995). Serotonin, schizophrenia and antipsychotic drug action.(3), 187?202.

Brenhouse, H. C., & Andersen, S. L. (2011). Nonsteroidal anti-inflammatory treatment prevents delayed effects of early life stress in rats.(5), 434?440.

Burguière, E., Monteiro, P., Feng, G., & Graybiel, A. M. (2013). Optogenetic stimulation of lateral orbitofronto- striatal pathway suppresses compulsive behaviors.(6137), 1243?1246.

Buzsàki, G., & Eidelberg, E. (1981). Commissural projection to the dentate gyrus of the rat: evidence for feed-forward inhibition.(1-2), 346?350.

Cabungcal, J. H., Counotte, D. S., Lewis, E. M., Tejeda, H. A., Piantadosi, P., Pollock, C., ... O’Donnell, P. (2014). Juvenile antioxidant treatment prevents adult deficits in a developmental model of schizophrenia.(5), 1073?1084.

Cabungcal, J. H., Steullet, P., Kraftsik, R., Cuenod, M., & Do, K. Q. (2013). Early-life insults impair parvalbumin interneurons via oxidative stress: reversal by N-acetylcysteine.(6), 574?582.

Cabungcal, J. H., Steullet, P., Morishita, H., Kraftsik, R., Cuenod, M., Hensch, T. K., & Do, K. Q. (2013). Perineuronal nets protect fast-spiking interneurons against oxidative stress.(22), 9130?9135.

Caillard, O., Moreno, H., Schwaller, B., Llano, I., Celio, M. R., & Marty, A. (2000). Role of the calcium-binding protein parvalbumin in short-term synaptic plasticity.(24), 13372?13377.

Cardin, J. A., Carlén, M., Meletis, K., Knoblich, U., Zhang, F., Deisseroth, K., ... Moore, C. I. (2009). Driving fast-spiking cells induces gamma rhythm and controls sensory responses.(7247), 663?667.

Carlen, M., Meletis, K., Siegle, J. H., Cardin, J. A., Futai, K., Vierling-Claassen, D., ... Tsai, L. H. (2012). A critical role for NMDA receptors in parvalbumin interneurons for gamma rhythm induction and behavior.(5), 537?548.

Celio, M. R., & Heizmann, C. W. (1981). Calcium-binding protein parvalbumin as a neuronal marker.(5830), 300?302.

Cohen, S. M., Tsien, R. W., Goff, D. C., & Halassa, M. M. (2015). The impact of NMDA receptor hypofunction on GABAergic neurons in the pathophysiology of schizophrenia.(1-3), 98?107.

Cunningham, M. O., Hunt, J., Middleton, S., LeBeau, F. E., Gillies, M. G., Davies, C. H., ... Racca, C. (2006). Region-specific reduction in entorhinal gamma oscillationsand parvalbumin-immunoreactive neurons in animal models of psychiatric illness.(10), 2767?2776.

Davis, K. L., & Kahn, R. S. (1991). Dopamine in schizophrenia: a review and reconceptualization.(11), 1474?1486.

Del Pino, I., García-Frigola, C., Dehorter, N., Brotons-Mas, J. R., Alvarez-Salvado, E., de Lagrán, M. M., ... Rico, B. (2013). Erbb4 deletion from fast-spiking interneurons causes schizophrenia-like phenotypes.(6), 1152?1168.

Dell'Anna, E., Geloso, M. C., Magarelli, M., & Molinari, M. (1996). Development of GABA and calcium binding proteins immunoreactivity in the rat hippocampus following neonatal anoxia.,(2), 93?96.

Demiralp, T., Herrmann, C. S., Erdal, M. E., Ergenoglu, T., Keskin, Y. H., Ergen, M., & Beydagi, H. (2006). DRD4 and DAT1 polymorphisms modulate human gamma band responses.(5), 1007?1019.

Do, K. Q., Cabungcal, J. H., Frank, A., Steullet, P., & Cuenod, M. (2009). Redox dysregulation, neurodevelopment, and schizophrenia.,(2), 220?230.

Donato, F., Rompani, S. B., & Caroni, P. (2013). Parvalbumin- expressing basket-cell network plasticity induced by experience regulates adult learning.(7479), 272?276.

Fagiolini, M., Fritschy, J. M., L?w, K., M?hler, H., Rudolph, U., & Hensch, T. K. (2004). Specific GABAA circuits for visual cortical plasticity.(5664), 1681?1683.

Featherstone, R. E., Rizos, Z., Nobrega, J. N., Kapur, S., & Fletcher, P. J. (2007). Gestational methylazoxymethanol acetate treatment impairs select cognitive functions: parallels to schizophrenia.(2), 483?492.

Fisahn, A., Neddens, J., Yan, L., & Buonanno, A. (2008). Neuregulin-1 modulates hippocampal gamma oscillations: implications for schizophrenia.(3), 612?618.

Flatow, J., Buckley, P., & Miller, B. J. (2013). Meta-analysis of oxidative stress in schizophrenia.(6), 400?409.

Flynn, G., Alexander, D., Harris, A., Whitford, T., Wong, W., Galletly, C., ... Williams, L. M. (2008). Increased absolute magnitude of gamma synchrony in first-episode psychosis.(1-3), 262?271.

Freund, T. F., & Buzsáki, G. (1996). Interneurons of the hippocampus.(4), 347?470.

Gárate, I., Garcia-Bueno, B., Madrigal, J. L. M., Caso, J. R., Alou, L., Gomez-Lus, M. L., ... Leza, J. C. (2013). Stress-induced neuroinflammation: role of the Toll-like receptor-4 pathway.(1), 32?43.

Ge, S., Goh, E. L. K., Sailor, K. A., Kitabatake, Y., Ming, G. L., & Song, H. (2006). GABA regulates synaptic integration of newly generated neurons in the adult brain.,(7076), 589?593.

Gill, K. M., & Grace, A. A. (2014). The role of α5 GABAA receptor agonists in the treatment of cognitive deficits in schizophrenia.(31), 5069?5076.

Gill, K. M., Lodge, D. J., Cook, J. M., Aras, S., & Grace, A. A. (2011). A novel α5GABAAR-positive allosteric modulator reverses hyperactivation of the dopamine system in the MAM model of schizophrenia.(9), 1903?1911.

Gogolla, N., LeBlanc, J. J., Quast, K. B., Südhof, T. C., Fagiolini, M., & Hensch, T. K. (2009). Common circuit defect of excitatory-inhibitory balance in mouse models of autism.,(2), 172?181.

Gonzalez-Burgos, G., & Lewis, D. A. (2008). GABA neurons and the mechanisms of network oscillations: implications for understanding cortical dysfunction in schizophrenia.(5), 944?961.

Gonzalez-Burgos, G., & Lewis, D. A. (2012). NMDA receptor hypofunction, parvalbumin-positive neurons, and cortical gamma oscillations in schizophrenia.(5), 950?957.

Grace, A. A. (2012). Dopamine system dysregulation by the hippocampus: implications for the pathophysiology and treatment of schizophrenia.(3), 1342?1348.

Gu, Y., Tran, T., Murase, S., Borrell, A., Kirkwood, A., & Quinlan, E. M. (2016). Neuregulin-Dependent Regulation of Fast-Spiking Interneuron Excitability Controls the Timing of the Critical Period.(40), 10285?10295.

Haig, A. R., Gordon, E., De Pascalis, V., Meares, R. A., Bahramali, H., & Harris, A. (2000). Gamma activity in schizophrenia: evidence of impaired network binding?(8), 1461?1468.

Halasy, K., & Somogyi, P. (1993). Distribution of GABAergic Synapses and Their Targets in the Dentate Gyrus of Rat: A quantitative Immunoelectron Microscopic Analysis.(3), 299?308.

Harte, M. K., Powell, S. B., Swerdlow, N. R., Geyer, M. A., & Reynolds, G. P. (2007). Deficits in parvalbumin and calbindin immunoreactive cells in the hippocampus of isolation reared rats.,(7), 893?898.

Hashimoto, T., Volk, D. W., Eggan, S. M., Mirnics, K., Pierri, J. N., Sun, Z., ... Lewis, D. A. (2003). Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia.(15), 6315?6326.

He, L. J., Liu, N., Cheng, T. L., Chen, X. J., Li, Y. D., Shu, Y. S., ... Zhang, X. H. (2014). Conditional deletion of Mecp2 in parvalbumin-expressing GABAergic cells results in the absence of critical period plasticity.(5036)

Heckers, S., 2004. The hippocampus in schizophrenia.(11), 2138–2139.

Howes, O. D., & Kapur, S. (2009). The dopamine hypothesis of schizophrenia: version III?the final common pathway.(3), 549?562.

Hu, H., Gan, J., & Jonas, P. (2014). Fast-spiking, parvalbumin+ GABAergic interneurons: From cellular design to microcircuit function.(6196), 1255263.

Hunt, M. J., Kopell, N. J., Traub, R. D., & Whittington, M. A. (2017). Aberrant network activity in schizophrenia.,(6), 371?382.

Javitt, D. C., & Zukin, S. R. (1991). Recent advances in the phencyclidine model of schizophrenia.(10), 1301?1308.

Jentsch, J. D., & Roth, R. H. (1999). The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia.(3), 201?225.

Jiang, Z., Rompala, G. R., Zhang, S., Cowell, R. M., & Nakazawa, K. (2013). Social isolation exacerbates schizophrenia-like phenotypes via oxidative stress in cortical interneurons.(10), 1024?1034.

Katagiri, H., Fagiolini, M., & Hensch, T. K. (2007). Optimization of somatic inhibition at critical period onset in mouse visual cortex.(6), 805?812.

Kaur, C., Rathnasamy, G., & Ling, E. A. (2013). Roles of activated microglia in hypoxia induced neuroinflammation in the developing brain and the retina.(1), 66?78.

Kim, H., ?hrlund-Richter, S., Wang, X., Deisseroth, K., & Carlén, M. (2016). Prefrontal parvalbumin neurons in control of attention.(1-2), 208?218.

Kim, S. Y., Cohen, B. M., Chen, X., Lukas, S. E., Shinn, A. K., Yuksel, A. C., ... ?ngür, D. (2016). Redox dysregulation in schizophrenia revealed by in vivo NAD+/NADH measurement.(1), 197?204.

Kinney, J. W., Davis, C. N., Tabarean, I., Conti, B., Bartfai, T., & Behrens, M. M. (2006). A specific role for NR2A-containing NMDA receptors in the maintenance of parvalbumin and GAD67 immunoreactivity in cultured interneurons.(5), 1604?1615.

Klausberger, T., & Somogyi, P. (2008). Neuronal diversity and temporal dynamics: the unity of hippocampal circuit operations.(5885), 53?57.

Kobayashi, M., & Buckmaster, P. S. (2003). Reduced inhibition of dentate granule cells in a model of temporal lobe epilepsy.,(6), 2440?2452.

Kocsis, B. (2012). Differential role of NR2A and NR2B subunits in N-methyl-D-aspartate receptor antagonist-inducedaberrant cortical gamma oscillations.(11), 987?995.

Komitova, M., Xenos, D., Salmaso, N., Tran, K. M., Brand, T., Schwartz, M. L., ... Vaccarino, F. M. (2013). Hypoxia-induced developmental delays of inhibitory interneurons are reversed by environmental enrichment in the postnatal mouse forebrain.(33), 13375?13387.

Konradi, C., Yang, C. K., Zimmerman, E. I., Lohmann, K. M., Gresch, P., Pantazopoulos, H., ... Heckers, S. (2011). Hippocampal interneurons are abnormal in schizophrenia.(1-3), 165?173.

Korotkova, T., Fuchs, E. C., Ponomarenko, A., von Engelhardt, J., & Monyer, H. (2010). NMDA receptor ablation on parvalbumin-positive interneurons impairs hippocampal synchrony, spatial representations, and working memory.(3), 557?569.

Kraguljac, N.V., White, D.M., Reid, M.A., Lahti, A.C. (2013). Increased hippocampal glutamate and volumetric deficits in unmedicated patients with schizophrenia.(12), 1294–1302.

Krystal, J. H., Karper, L. P., Seibyl, J. P., Freeman, G. K., Delaney, R., Bremner, J. D., ... Charney, D. S. (1994). Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans: psychotomimetic, perceptual, cognitive, and neuroendocrine responses.(3), 199?214.

Kuhlman, S. J., Olivas, N. D., Tring, E., Ikrar, T., Xu, X., & Trachtenberg, J. T. (2013). A disinhibitory microcircuit initiates critical-period plasticity in the visual cortex.(7468), 543?546.

Kwon, J. S., O'donnell, B. F., Wallenstein, G. V., Greene, R. W., Hirayasu, Y., Nestor, P. G., ... McCarley, R. W. (1999). Gamma frequency–range abnormalities to auditory stimulation in schizophrenia.(11), 1001?1005.

Lewis, D. A., Curley, A. A., Glausier, J. R., & Volk, D. W. (2012). Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia.(1), 57?67.

Lewis, D. A., Hashimoto, T., & Volk, D. W. (2005). Cortical inhibitory neurons and schizophrenia.(4), 312?324.

Lisman, J. E., Coyle, J. T., Green, R. W., Javitt, D. C., Benes, F. M., Heckers, S., & Grace, A. A. (2008). Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia.(5), 234?242.

Lodge, D. J., Behrens, M. M., & Grace, A. A. (2009). A loss of parvalbumin-containing interneurons is associated with diminished oscillatory activity in an animal model of schizophrenia.(8), 2344?2354.

Luby, E. D., Cohen, B. D., Rosenbaum, G., Gottlieb, J. S., & Kelley, R. (1959). Study of a new schizophrenomimetic drug?Sernyl.(3), 363?369.

Malaspina, D., Storer, S., Furman, V., Esser, P., Printz, D., Berman, A., ... Van Heertum, R. (1999). SPECT study of visual ?xation in schizophrenia and comparison subjects.(1), 89–93.

Marín, O. (2012). Interneuron dysfunction in psychiatric disorders.(2), 107?120.

Markram, H., Toledo-Rodriguez, M., Wang, Y., Gupta, A., Silberberg, G., & Wu, C. (2004). Interneurons of the neocortical inhibitory system.(10), 793?807.

Mauney, S. A., Athanas, K. M., Pantazopoulos, H., Shaskan, N., Passeri, E., Berretta, S., & Woo, T. U. W. (2013). Developmental pattern of perineuronal nets in the human prefrontal cortex and their deficit in schizophrenia.(6), 427?435.

Medoff, D.R., Holcomb, H.H., Lahti, A.C., Tamminga, C.A. (2001). Probing the human hippocampus using rCBF: Contrasts in schizophrenia.(5), 543?550

Meyer, U., Nyffeler, M., Yee, B. K., Knuesel, I., & Feldon, J. (2008). Adult brain and behavioral pathological markers of prenatal immune challenge during early/middle and late fetal development in mice.,(4), 469?486.

Miles, R. (1990). Synaptic excitation of inhibitory cells by single CA3 hippocampal pyramidal cells of the guinea-pig in vitro.,(1), 61?77.

Morris, H. M., Hashimoto, T., & Lewis, D. A. (2008). Alterations in somatostatin mRNA expression in the dorsolateral prefrontal cortex of subjects with schizophreniaor schizoaffective disorder.(7), 1575?1587.

Olney, J. W., & Farber, N. B. (1995). NMDA antagonists as neurotherapeutic drugs, psychotogens, neurotoxins, and research tools for studying schizophrenia.(4), 335?345.

Pantazopoulos, H., Lange, N., Baldessarini, R. J., & Berretta, S. (2007). Parvalbumin neurons in the entorhinal cortex of subjects diagnosed with bipolar disorder or schizophrenia.(5), 640?652.

Pantazopoulos, H., Woo, T. U. W., Lim, M. P., Lange, N., & Berretta, S. (2010). Extracellular matrix-glial abnormalitiesin the amygdala and entorhinal cortex of subjects diagnosed with schizophrenia.(2), 155?166.

Pouille, F., & Scanziani, M. (2001). Enforcement of temporal fidelity in pyramidal cells by somatic feed-forward inhibition.(5532), 1159?1163.

Pouille, F., & Scanziani, M. (2004). Routing of spike series by dynamic circuits in the hippocampus.(6993), 717?723.

Romón, T., Mengod, G., & Adell, A. (2011). Expression of parvalbumin and glutamic acid decarboxylase-67 after acute administration of MK-801. Implications for the NMDAhypofunction model of schizophrenia.(2), 231?238.

Rossier, J., Bernard, A., Cabungcal, J. H., Perrenoud, Q., Savoye, A., Gallopin, T., ... Lein, S. (2015). Cortical fast-spiking parvalbumin interneurons enwrapped in the perineuronal net express the metallopeptidases Adamts8, Adamts15 and Neprilysin.(2), 154?161.

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.(2), 69?77.

Schiavone, S., Sorce, S., Dubois-Dauphin, M., Jaquet, V., Colaianna, M., Zotti, M., ... Krause, K. H. (2009). Involvement of NOX2 in the development of behavioral and pathologic alterations in isolated rats.(4), 384?392.

Schobel, S. A., Lewandowski, N. M., Corcoran, C. M., Moore, H., Brown, T., Malaspina, D., Small, S. A. (2009). Differential targeting of the CA1 sub?eld of the hippocampalformation by schizophrenia and related psychotic disorders.(9), 938–946

Shang, C., Liu, Z., Chen, Z., Shi, Y., Wang, Q., Liu, S., ... Cao, P. (2015). A parvalbumin-positive excitatory visual pathway to trigger fear responses in mice.(6242), 1472?1477.

Spencer, K. M., Nestor, P. G., Niznikiewicz, M. A., Salisbury, D. F., Shenton, M. E., & McCarley, R. W. (2003). Abnormal neural synchrony in schizophrenia.(19), 7407?7411.

Spencer, K. M., Niznikiewicz, M. A., Shenton, M. E., & McCarley, R. W. (2008). Sensory-evoked gamma oscillations in chronic schizophrenia.(8), 744?747.

Sohal, V. S., Zhang, F., Yizhar, O., & Deisseroth, K. (2009). Parvalbumin neurons and gamma rhythms enhance cortical circuit performance.(7247), 698?702.

Song, J., Sun, J., Moss, J., Wen, Z., Sun, G. J., Hsu, D., ... Song, H. (2013). Parvalbumin interneurons mediate neuronal circuitry-neurogenesis coupling in the adult hippocampus.,(12), 1728?1730.

Stark, E., Eichler, R., Roux, L., Fujisawa, S., Rotstein, H. G., & Buzsáki, G. (2013). Inhibition-induced theta resonance in cortical circuits.(5), 1263?1276.

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.(7), 936?943.

Steullet, P., Cabungcal, J. H., Kulak, A., Kraftsik, R., Chen, Y., Dalton, T. P., ... Do, K. Q. (2010). Redox dysregulation affects the ventral but not dorsal hippocampus: impairment of parvalbumin neurons, gamma oscillations, and related behaviors.,(7), 2547?2558.

Suh, J., Foster, D. J., Davoudi, H., Wilson, M. A., & Tonegawa, S. (2013). Impaired hippocampal ripple-associated replay in a mouse model of schizophrenia.(2), 484?493.

Todtenkopf, M. S., & Benes, F. M. (1998). Distribution of glutamate decarboxylase65 immunoreactive puncta on pyramidal and nonpyramidal neurons in hippocampus of schizophrenic brain.(4), 323?332.

Tremblay, R., Lee, S., & Rudy, B. (2016). GABAergic interneurons in the neocortex: from cellular properties to circuits.(2), 260?292.

Tsai, G., & Coyle, J. T. (2002). Glutamatergic mechanisms in schizophrenia.(1), 165?179.

Uhlhaas, P. J., Linden, D. E. J., Singer, W., Haenschel, C., Lindner, M., Maurer, K., & Rodriguez, E. (2006). Dysfunctional long-range coordination of neural activity during Gestalt perception in schizophrenia.31), 8168?8175.

Uhlhaas, P. J., & Singer, W. (2010). Abnormal neural oscillations and synchrony in schizophrenia.(2), 100?113.

Volk, D. W., Gonzalez-Burgos, G., & Lewis, D. A. (2016). l-Proline, GABA synthesis and gamma oscillations in schizophrenia.(12), 797?798.

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.,(40), 13314?13325.

Wolff, S. B. E., Gründemann, J., Tovote, P., Krabbe, S., Jacobson, G. A., Müller, C., ... Lüthi, A. (2014). Amygdala interneuron subtypes control fear learning through disinhibition.(7501), 453?458.

Yao, J. K., & Keshavan, M. S. (2011). Antioxidants, redox signaling, and pathophysiology in schizophrenia: an integrative view.(7), 2011?2035.

Zhang, Y., Behrens, M. M., & Lisman, J. E. (2008). Prolonged exposure to NMDAR antagonist suppresses inhibitory synaptic transmission in prefrontal cortex.(2), 959?965.

Zhang, Z. J., & Reynolds, G. P. (2002). A selective decrease in the relative density of parvalbumin-immunoreactive neurons in the hippocampus in schizophrenia.(1-2), 1?10.

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