生物谷报道:强迫症(Obsessive compulsive disorder,缩写OCD)即强迫性神经症,是一种精神官能症,更具体地说,是焦虑症的一种。现在,美国杜克大学华裔教授冯国平研究小组的研究人员利用基因工程方法使小鼠表现出了类似OCD症状的行为特质,并且通过抗抑郁剂和靶向一个关键大脑环路使小鼠行为恢复正常。
研究人员培养了一种缺失一个特殊基因的小鼠,并且发现一个与OCD有关的大脑环路中出现缺陷。和人类OCD患者情况相似,这些小鼠出现强迫性自我修饰(compulsive grooming)——反复抓自己的脸(小鼠通过抓摸来“洗脸”),直到毛皮破损,甚至流血,还无法停止,同时还会焦躁不安。当将这种丢失的基因重新插回该环路时,小鼠的行为和缺陷有了很大的转变。这种特殊的基因叫做SAPAP3,该基因编码一种能够帮助脑细胞通过谷氨酸化学信使系统进行交流的蛋白质。
由于该研究首次将OCD类似行为与特定大脑环路中的谷氨酸系统的异常联系在一起,因此可能为药物开发提供新的靶标。
Sapap3是Sapap家族蛋白质中,唯一在纹状体中“任职”的一位。它缺位时,一些信息传导会出现“一边倒”。比如,正常情况下,小鼠感觉脸脏了,抓几下就会感到干净了,但没有Sapap3时,“脸干净”的信息怎么也传不回大脑,于是小鼠就会不停地重复一个动作,无法停止。科研小组用基因治疗的方法,让这种蛋白重新回到纹状体中,小鼠马上就停止了抓脸,焦虑症状也减轻了。
冯国平解释说,此前,对于强迫症的研究多集中在五-羟色胺上,但这个研究却开辟了新的研究视角,不仅揭示了强迫症的生理机制,还为药物研发提供新的靶点。据统计,全球人口中约有2%患有不同程度的强迫症。“这项研究将为强迫症患者带来福音。”早年从事强迫症研究的美国国立心理健康研究所主任托马斯·R·英瑟儿对这项成果的临床应用前景十分看好。
冯国平,浙江桐庐人,现任杜克大学神经生物学系助理教授。1982年毕业于浙江医科大学。1986年在上海第二医科大学取得硕士学位。1989-1995年在纽约州立大学水牛城分校攻读博士学位。1995-2000年在华盛顿大学师从著名生物学家Josh Sanes从事博士后研究。期间系统揭示了乙酰胆碱能神经突触的发育机理,同时创建了为神经生物学界广泛应用的绿色荧光蛋白转基因小鼠模型(GFP transgenic mice)。2000年受聘于杜克大学。科研论文曾在《细胞》、《科学》、《神经元》和《自然-神经科学》等顶级生物学杂志上发表。在美期间,十多次获得学术嘉奖,包括 Alfred Sloan Research Fellowship, Broad Scholar Award, Mcknight Neuroscience of Brain Disorders Award等。
强迫性神经症: 强迫性神经症是一种神经官能症,简称强迫症,以反复出现强迫观念和强迫动作为基本特征的一类神经症性障碍。强迫症在精神科患者中占0.1%~0.46%,在一般人口中约占0.05%。该病多在30岁以前发病,男多于女,以脑力劳动者常见。某些强烈的精神因素作为起病诱因,强而不均衡型的人易患本病,其性格主观、任性、急躁、好胜、自制能力差,少数患者具有精神薄弱性格,自幼胆小怕事、怕犯错误、对自己的能力缺乏信心,遇事十分谨慎,反复思想,事后不断嘀咕并多次检查,总希望达到尽善尽美。在众人面前十分拘谨,容易发窘,对自己过分克制,要求严格,生活习惯较为呆板,墨守成规,兴趣和爱好不多,对现实生活中的具体事物注意不够,但对可能发生的事情特别关注,甚至早就为之担忧,工作认真负责,但主动性往往不足。
原始出处:
Nature 448, 894-900 (23 August 2007) | doi:10.1038/nature06104; Received 30 May 2007; Accepted 16 July 2007
Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice
Jeffrey M. Welch1,9, Jing Lu1,4,9, Ramona M. Rodriguiz2, Nicholas C. Trotta1, Joao Peca1,5, Jin-Dong Ding6, Catia Feliciano1,7, Meng Chen3, J. Paige Adams8, Jianhong Luo4, Serena M. Dudek8, Richard J. Weinberg6, Nicole Calakos1,3, William C. Wetsel2 & Guoping Feng1
Department of Neurobiology,
Departments of Psychiatry and Behavioral Sciences, Cell Biology, Neurobiology, and Mouse Behavioral and Neuroendocrine Analysis Core Facility,
Division of Neurology, Center for Translational Neuroscience, Duke University Medical Center, Durham, North Carolina 27710, USA
Department of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal
Department of Cell and Developmental Biology, Neuroscience Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA
Gulbenkian PhD Programme in Biomedicine, Gulbenkian Science Institute, 2781-901 Oeiras, Portugal
National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA
These authors contributed equally to this work.
Correspondence to: Guoping Feng1 Correspondence and requests for materials should be addressed to G.F. (Email: feng@neuro.duke.edu).
Obsessive-compulsive disorder (OCD) is an anxiety-spectrum disorder characterized by persistent intrusive thoughts (obsessions) and repetitive actions (compulsions). Dysfunction of cortico-striato-thalamo-cortical circuitry is implicated in OCD, although the underlying pathogenic mechanisms are unknown. SAP90/PSD95-associated protein 3 (SAPAP3; also known as DLGAP3) is a postsynaptic scaffolding protein at excitatory synapses that is highly expressed in the striatum. Here we show that mice with genetic deletion of Sapap3 exhibit increased anxiety and compulsive grooming behaviour leading to facial hair loss and skin lesions; both behaviours are alleviated by a selective serotonin reuptake inhibitor. Electrophysiological, structural and biochemical studies of Sapap3-mutant mice reveal defects in cortico-striatal synapses. Furthermore, lentiviral-mediated selective expression of Sapap3 in the striatum rescues the synaptic and behavioural defects of Sapap3-mutant mice. These findings demonstrate a critical role for SAPAP3 at cortico-striatal synapses and emphasize the importance of cortico-striatal circuitry in OCD-like behaviours.