Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research , Jakkur, Bengaluru 560 064, Karnataka, India.
Open Biol. 2019 Jun 28;9(6):180265. doi: 10.1098/rsob.180265. Epub 2019 Jun 12.
Normal brain development is highly dependent on the timely coordinated actions of genetic and environmental processes, and an aberration can lead to neurodevelopmental disorders (NDDs). Intellectual disability (ID) and autism spectrum disorders (ASDs) are a group of co-occurring NDDs that affect between 3% and 5% of the world population, thus presenting a great challenge to society. This problem calls for the need to understand the pathobiology of these disorders and to design new therapeutic strategies. One approach towards this has been the development of multiple analogous mouse models. This review discusses studies conducted in the mouse models of five major monogenic causes of ID and ASDs: Fmr1, Syngap1, Mecp2, Shank2/3 and Neuroligins/Neurnexins. These studies reveal that, despite having a diverse molecular origin, the effects of these mutations converge onto similar or related aetiological pathways, consequently giving rise to the typical phenotype of cognitive, social and emotional deficits that are characteristic of ID and ASDs. This convergence, therefore, highlights common pathological nodes that can be targeted for therapy. Other than conventional therapeutic strategies such as non-pharmacological corrective methods and symptomatic alleviation, multiple studies in mouse models have successfully proved the possibility of pharmacological and genetic therapy enabling functional recovery.
正常的大脑发育高度依赖于遗传和环境过程的适时协调作用，而异常则可能导致神经发育障碍（NDD）。智力障碍（ID）和自闭症谱系障碍（ASD）是一组同时发生的 NDD，影响着全球 3%至 5%的人口，因此给社会带来了巨大挑战。这个问题需要我们了解这些疾病的病理生物学，并设计新的治疗策略。为此，人们开发了多种类似的小鼠模型。本文综述了在 Fmr1、Syngap1、Mecp2、Shank2/3 和神经连接蛋白/神经连接素等 ID 和 ASD 的五个主要单基因病因的小鼠模型中开展的研究。这些研究表明，尽管这些突变具有不同的分子起源，但它们的影响集中在相似或相关的病因途径上，从而导致 ID 和 ASD 的典型认知、社交和情感缺陷表型。这种趋同突显了可作为治疗靶点的共同病理节点。除了非药物治疗等传统治疗策略外，多项小鼠模型研究成功证明了药物和基因治疗实现功能恢复的可能性。
