Bridging the translational gap: what can synaptopathies tell us about autism?
Bridging the translational gap: what can synaptopathies tell us about autism?
复制标题
弥合翻译差距：突触病可以告诉我们关于自闭症的什么信息？
DOI：
10.3389/fnmol.2023.1191323
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发表时间：
2023
影响因子：
4.8
通讯作者：
Gallagher, Louise
中科院分区：
文献类型：
--
作者：
Molloy, Ciara J. J.;Cooke, Jennifer;Gatford, Nicholas J. F.;Rivera-Olvera, Alejandro;Avazzadeh, Sahar;Homberg, Judith R. R.;Grandjean, Joanes;Fernandes, Cathy;Shen, Sanbing;Loth, Eva;Srivastava, Deepak P. P.;Gallagher, Louise
关键词：
自闭症和其他神经发育疾病的神经生物学涉及多种分子途径和细胞过程。目前关注的焦点是突触基因状况，或突触病变，指的是与罕见遗传变异相关的临床状况，这些变异破坏了参与突触生物学的基因。突触病变通常与自闭症和发育迟缓有关，并可能与一系列其他神经精神疾病有关。临床前和临床研究表明，自闭症患者早期大脑结构发育的差异以及谷氨酸能和gaba能神经传递的改变可能会扰乱兴奋和抑制平衡，这表明突触生物学的改变。本文主要对NRXN-NLGN-SHANK通路进行综述，该通路与突触组装、突触传递信号和突触功能有关。我们提供了对该途径的临床前分子研究的见解概述。聚焦于NRXN1缺失和SHANK3突变，我们讨论了来自突触病变个体的诱导多能干细胞（iPSC）模型对细胞过程和电生理的新认识，NRXN1和SHANK3突触基因条件动物模型的神经影像学和行为发现，以及突触病变人类临床研究中关于自闭症特征、大脑和行为表型的关键发现。从临床前模型中鉴定基于分子的生物标志物旨在促进靶向治疗的发展。然而，将临床前动物模型和iPSC研究转化为解释人类大脑发育和自闭症特征仍然具有挑战性。我们讨论了临床前和临床突触病研究中存在的挑战，以及在临床前和临床研究中协调方法的潜在解决方案。弥合临床前和临床研究之间的转化差距对于理解生物学机制，确定靶向治疗，并最终朝着个性化治疗复杂神经发育疾病（如自闭症）的方法发展是必要的。
Multiple molecular pathways and cellular processes have been implicated in the neurobiology of autism and other neurodevelopmental conditions. There is a current focus on synaptic gene conditions, or synaptopathies, which refer to clinical conditions associated with rare genetic variants disrupting genes involved in synaptic biology. Synaptopathies are commonly associated with autism and developmental delay and may be associated with a range of other neuropsychiatric outcomes. Altered synaptic biology is suggested by both preclinical and clinical studies in autism based on evidence of differences in early brain structural development and altered glutamatergic and GABAergic neurotransmission potentially perturbing excitatory and inhibitory balance. This review focusses on the NRXN-NLGN-SHANK pathway, which is implicated in the synaptic assembly, trans-synaptic signalling, and synaptic functioning. We provide an overview of the insights from preclinical molecular studies of the pathway. Concentrating on NRXN1 deletion and SHANK3 mutations, we discuss emerging understanding of cellular processes and electrophysiology from induced pluripotent stem cells (iPSC) models derived from individuals with synaptopathies, neuroimaging and behavioural findings in animal models of Nrxn1 and Shank3 synaptic gene conditions, and key findings regarding autism features, brain and behavioural phenotypes from human clinical studies of synaptopathies. The identification of molecular-based biomarkers from preclinical models aims to advance the development of targeted therapeutic treatments. However, it remains challenging to translate preclinical animal models and iPSC studies to interpret human brain development and autism features. We discuss the existing challenges in preclinical and clinical synaptopathy research, and potential solutions to align methodologies across preclinical and clinical research. Bridging the translational gap between preclinical and clinical studies will be necessary to understand biological mechanisms, to identify targeted therapies, and ultimately to progress towards personalised approaches for complex neurodevelopmental conditions such as autism.
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影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
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Marchini J
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11
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Fuccillo MV
影响因子：
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通讯作者：
Dobyns, William B.
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通讯作者：
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