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Excitatory-inhibitory Imbalance and Autism Spectrum Disorder: Mechanism and Treatment Progress
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摘要: 孤独症谱系障碍(autism spectrum disorder, ASD)是世界上患病率增长最快的神经发育障碍，该病具有显著的遗传异质性，给临床治疗带来了巨大挑战。研究表明，中枢神经系统的兴奋-抑制(excitatory-inhibitory，E-I)失衡可能是ASD的重要发病机制之一，在多种ASD动物模型中进行神经环路E-I失衡调节，能够改善模型动物的孤独症样行为。相关临床试验将E-I失衡作为ASD的治疗靶点，恢复特定皮质区域原有的E-I平衡状态，能够对ASD患者起到一定的治疗作用。本文就E-I失衡在ASD中的作用机制及E-I失衡调节剂治疗ASD的研究进展作一综述，以期为ASD的临床诊疗提供新思路。Abstract: Autism spectrum disorder (ASD) is becoming one of the fastest growing neurodevelopmen-tal disorders around the world, yet its clinical treatment still faces challenge due to the heterogeneity in etiology and symptom phenotypes. It is believed that excitatory-inhibitory (E-I) imbalance in the central nervous system may play an important role in the pathogenic mechanisms of ASD. E-I imbalances in synaptic transmission and neural circuits are frequently observed in different animal models of ASD, and the corresponding reversion normalizes the autism-like behaviors in these animals. Some E-I modulators have been tested for their therapeutic potential on ASD patients with encouraging results. This article expounds the mechanism of E-I imbalance in ASD and E-I imbalance regulators treatment progress, to provide new insights on the therapeutic targets for ASD.
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研讨式(Seminar)教学法是将“以教师为中心”的传统教学模式转变为“以学生为中心”的新型教学模式，能够充分调动学生的主动性和积极性，加深其对课程内容的理解、培养科研思维及能力，以实现“教”与“学”的双重获益。随着我国医学教育体制改革的发展，以Seminar为代表的教学与科研相结合的模式成为目前主要教学模式[1-4]。然而，Seminar教学法存在流于形式(如变相的问答式教学)、难以保证学生的参与度等不足[5]。案例教学法(case-based learning，CBL)则以典型案例为载体提出问题，引导学生主动学习，加深对基本原理和概念的理解，已广泛应用于医药领域教学实践中[6-9]。然而，典型案例的选取、案例的深度剖析及引导等降低了CBL的实施效果[5]。Seminar教学法与CBL教学法相结合，可提升学生的理论和实践能力，拓展其科研视野, 促进学生按照“理论学习—案例分析—实践思考—知识巩固”这一模式实现专业知识的融会贯通。
新时代背景下的课程思政是积极贯彻习近平总书记在全国教育大会上的重要讲话精神、落实“立德树人”根本任务的重要方式。在临床药理学课程中融入课程思政教学能够培养学生的责任心和高尚医德。目前，抗肿瘤药物的临床药理课程教学中存在学生肿瘤药理专业基础知识薄弱、传统讲授方法导致“教”与“学”分离、教材内容陈旧且滞后、学生积极性不高等问题。因此，本文以部分课程教学为例，探讨“Seminar-CBL-课程思政”创新模式在临床药理学教学实践中的作用，以期激发学生的学习兴趣，培养学生正确的世界观、人生观、价值观，实现“教”与“学”双重目标，为优化临床药理学教育提供借鉴。
1. “Seminar-CBL-课程思政”教学模式
以我国自主研发的创新性抗肿瘤分子靶向药物埃克替尼的临床药动学研究为例，指导学生结合“临床药动学”授课内容及各自研究方向进行自我学习，加深对理论知识点的认识和理解，具体教学步骤如下。
1.1 融合理论知识、结合典型案例开展“Seminar-CBL”教学
教师在提高自身专业素养的同时应转变思维，提倡“以学生为主”的教学模式。首先由授课教师进行基础知识讲解，再由小组代表进行专题汇报讲解，内容包括埃克替尼的药理作用及相关机制，文献的目的、方法、结果、结论等，并就典型案例进行交流，阐述文献思路、指出文献中存在的局限性、提出改进方案、开展自我学习或小组学习。最后，由授课教师对本次研讨中的案例进行指导和纠偏、梳理教材中“临床药动学”相关内容。
1.2 挖掘课程思政要素
在上述“Seminar-CBL”教学基础上，结合我国医药技术的快速发展进程，介绍我国近代自主研发的抗肿瘤分子靶向创新药物埃克替尼，增强学生的民族自豪感和爱国情怀。以埃克替尼的吸收、分布、代谢和排泄存在个体差异，需制订个体化的治疗方案为例，阐述唯物辩证法的观点，在矛盾普遍性原理指导下具体分析矛盾特殊性的唯物主义思想，引导学生树立科学的世界观，强化对祖国医药事业快速发展的人文情怀。在埃克替尼药理作用机制方面，通过讲授开展临床药理学研究中涉及的动物伦理及医学伦理，传递“防病治病、救死扶伤、保护人民健康”的医德医风；通过讲授埃克替尼临床试验中发生的不良事件和及时处置，传递医生、护士、药师、技师等不同科室和专业人员的通力协作精神。
1.3 建立“Seminar-CBL-课程思政”创新模式教学案例库
结合课程特色编写体现临床药理学逻辑特点及课程思政要求的教材，初步建立临床药理学创新授课模式的教学案例库，并成立教学督导组，以创新模式的融入程度、教学方法和思想引导等作为教师教学考核的重要指标。此外，将教学过程中如何体现以下课程思政要素作为重要的考核指标之一，包括但不限于：“诚信守法”的职业规范、“救死扶伤，医者仁心”的医德医风、“科学严谨”的敬业精神、“不惧艰难，勇攀高峰”的创新精神、“大公无私，人民至上”的爱国情怀、“以人为本”的价值体现(人文关怀、用药安全、精准用药)等。
2. 教学效果评价与反馈
2022—2023学年第一学期接受《临床药理学》课程教学的首都医科大学“5+3”一体化2019级共47名学生接受“Seminar-CBL-课程思政”创新模式教学，随机分为5个研讨小组，每组约10名学生。组内成员根据学习成绩及服务意识自荐或推选一名组长，由组长进行任务分工，选择埃克替尼临床药理学研究中的典型案例完成课件制作及主题发言稿。组内成员按照本次研讨的准备程度、语言表达能力、逻辑思维能力及应变能力，选择其中1人作为代表进行汇报展示，全体组员筹划研讨小论文初稿。
教师通过考察学生在检索文献及观点提炼、现场演讲及回答问题、与其他学生交流探讨等方面的能力评价“Seminar-CBL-课程思政”创新模式的教学效果。具体评价方式包括教师评分、学生互评，评审专家现场评价等。具体考核指标主要包括论文讲解的正确性、现场幻灯片制作质量、论文逻辑思路、内容凝练程度、回答问题的贴切度等，最终按照得分高低排名，遴选出综合成绩前三名的研讨小组。同时，教师也可邀请高年资教授担任点评人对案例分析及讨论内容进行提问、补充及学术述评，以考核学生对理论知识的熟悉程度。最后，由教师进行全面总结，提出需要改进的环节。
3. 讨论
“Seminar-CBL- 课程思政”创新模式不仅解决了Seminar模式程序化和学生发言不积极的瓶颈问题，且通过典型案例讲解改进了教师主导的填鸭式教学模式，有助于学生对专业知识的整合和理解，营造多学科交叉的学术交流氛围，激发学生的创新思维，从而提高教学质量。此外，该模式倡导一种平等的互学助学关系，教师和学生是整个课程的“双中心”；同时，这一综合教学模式可实现学生“理论—实践—理论”的环路反馈，即把理论应用于案例实践，再通过案例实践发现理论的适应性和局限性，提升学生对理论的再认识，有助于学生对课堂知识的消化吸收。本研究中，通过小组成员集体查阅文献、梳理文献思路、制作幻灯片并现场汇报等形式进行教学，不仅创新授课形式，让学生亲身参与，且在教学过程中进一步升华了爱国主义教育等思政要素。
目前该模式仍存在一定的局限性：(1)教师方面：课前需精心准备课程内容和推荐授课典型案例、需具备一定专业素养和优秀的主持控场能力、易与课程思政要素(仁爱精神、医德医风等)脱节。(2)学生方面：需遵守研讨规则(如Seminar中不同部分的演讲时间、回答问题的逻辑性和严谨性)，主动参与度要求较高，需做好充分的准备并尝试回答专业问题，积极投入自学互学，共同提高研讨会的质量。(3)其他方面：要求师生课上课下保持互动交流、教学设施设置合理(需设置“回”字型座椅便于师生面对面交流探讨)。
本文初步探讨了“Seminar-CBL-课程思政”创新教学模式在提升学生主动学习积极性、提高学生检索文献并汇报展示的能力、凝练“教”与“学”中的课程思政要素(如仁爱精神、创新精神及职业精神等)等方面的关键作用，助力学生对临床药理学知识的融会贯通，未来仍需进一步获取和分析具体评价指标以明确这一创新模式对于提升学生理论及实践能力的重要价值。
作者贡献：石岳负责文献检索及论文撰写；朱波、黄宇光负责论文设计及修订。利益冲突：所有作者均声明不存在利益冲突 -
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