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突触基因与神经发育障碍:从分子机制到行为测试的发育策略。

Synaptic genes and neurodevelopmental disorders: From molecular mechanisms to developmental strategies of behavioral testing.

机构信息

Department of Experimental Medicine, University of Genoa, Genoa, Italy; Center for Synaptic Neuroscience, Istituto Italiano di Tecnologia, Genoa, Italy.

Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Children's Hospital A. Meyer-University of Florence, Florence, Italy.

出版信息

Neurobiol Dis. 2022 Oct 15;173:105856. doi: 10.1016/j.nbd.2022.105856. Epub 2022 Sep 5.

Abstract

Synaptopathies are a class of neurodevelopmental disorders caused by modification in genes coding for synaptic proteins. These proteins oversee the process of neurotransmission, mainly controlling the fusion and recycling of synaptic vesicles at the presynaptic terminal, the expression and localization of receptors at the postsynapse and the coupling between the pre- and the postsynaptic compartments. Murine models, with homozygous or heterozygous deletion for several synaptic genes or knock-in for specific pathogenic mutations, have been developed. They have proved to be extremely informative for understanding synaptic physiology, as well as for clarifying the patho-mechanisms leading to developmental delay, epilepsy and motor, cognitive and social impairments that are the most common clinical manifestations of neurodevelopmental disorders. However, the onset of these disorders emerges during infancy and adolescence while the behavioral phenotyping is often conducted in adult mice, missing important information about the impact of synaptic development and maturation on the manifestation of the behavioral phenotype. Here, we review the main achievements obtained by behavioral testing in murine models of synaptopathies and propose a battery of behavioral tests to improve classification, diagnosis and efficacy of potential therapeutic treatments. Our aim is to underlie the importance of studying behavioral development and better focusing on disease onset and phenotypes.

摘要

突触病是一类由突触蛋白基因修饰引起的神经发育障碍。这些蛋白质监督神经传递过程,主要控制突触前末端突触小泡的融合和再循环、突触后受体的表达和定位以及前突触和后突触区之间的偶联。已经开发出了几种突触基因的纯合或杂合缺失或特定致病突变的基因敲入的小鼠模型。它们已被证明对于理解突触生理学非常有帮助,也有助于阐明导致发育迟缓、癫痫以及运动、认知和社交障碍的病理机制,这些是神经发育障碍的最常见临床表现。然而,这些障碍在婴儿和青少年时期开始出现,而行为表型通常在成年小鼠中进行,因此错过了关于突触发育和成熟对行为表型表现影响的重要信息。在这里,我们回顾了突触病小鼠模型中行为测试所取得的主要成果,并提出了一系列行为测试,以改善分类、诊断和潜在治疗效果。我们的目的是强调研究行为发育的重要性,并更好地关注疾病的发生和表型。

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