Deciphering autism heterogeneity: a molecular stratification approach in four mouse models.

IF 5.8 1区 医学 Q1 PSYCHIATRY Translational Psychiatry Pub Date : 2024-10-04 DOI:10.1038/s41398-024-03113-5
Caroline Gora, Ana Dudas, Océane Vaugrente, Lucile Drobecq, Emmanuel Pecnard, Gaëlle Lefort, Lucie P Pellissier
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Abstract

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by impairments in social interaction and communication, as well as restrained or stereotyped behaviors. The inherent heterogeneity within the autism spectrum poses challenges for developing effective pharmacological treatments targeting core features. Successful clinical trials require the identification of robust markers to enable patient stratification. In this study, we identified molecular markers within the oxytocin and immediate early gene families across five interconnected brain structures of the social circuit. We used wild-type and four heterogeneous mouse models, each exhibiting unique autism-like behaviors modeling the autism spectrum. While dysregulations in the oxytocin family were model-specific, immediate early genes displayed widespread alterations, reflecting global changes across the four models. Through integrative analysis, we identified Egr1, Foxp1, Homer1a, Oxt, and Oxtr as five robust and discriminant molecular markers that allowed the successful stratification of the four models. Importantly, our stratification demonstrated predictive values when challenged with a fifth mouse model or identifying subgroups of mice potentially responsive to oxytocin treatment. Beyond providing insights into oxytocin and immediate early gene mRNA dynamics, this proof-of-concept study represents a significant step toward the potential stratification of individuals with ASD. This work has implications for the success of clinical trials and the development of personalized medicine in autism.

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解读自闭症的异质性:四种小鼠模型的分子分层方法。
自闭症谱系障碍(ASD)是一种复杂的神经发育疾病,其特点是社交互动和沟通障碍,以及抑制或刻板行为。自闭症谱系中固有的异质性为开发针对核心特征的有效药物治疗带来了挑战。成功的临床试验需要确定可靠的标记物,以便对患者进行分层。在这项研究中,我们在社交回路的五个相互关联的大脑结构中鉴定了催产素和即刻早期基因家族中的分子标记物。我们使用了野生型小鼠和四种异质性小鼠模型,每种模型都表现出独特的自闭症谱系中的自闭症样行为。催产素家族的失调具有模型特异性,而即时早期基因则表现出广泛的改变,反映了四个模型的整体变化。通过综合分析,我们确定了 Egr1、Foxp1、Homer1a、Oxt 和 Oxtr 这五个稳健且具有鉴别性的分子标记,从而成功地对这四种模型进行了分层。重要的是,在挑战第五个小鼠模型或确定可能对催产素治疗有反应的小鼠亚群时,我们的分层显示出了预测价值。除了提供催产素和即刻早期基因 mRNA 动态的见解外,这项概念验证研究还向可能对 ASD 患者进行分层迈出了重要一步。这项工作对自闭症临床试验的成功和个性化药物的开发具有重要意义。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
11.50
自引率
2.90%
发文量
484
审稿时长
23 weeks
期刊介绍: Psychiatry has suffered tremendously by the limited translational pipeline. Nobel laureate Julius Axelrod''s discovery in 1961 of monoamine reuptake by pre-synaptic neurons still forms the basis of contemporary antidepressant treatment. There is a grievous gap between the explosion of knowledge in neuroscience and conceptually novel treatments for our patients. Translational Psychiatry bridges this gap by fostering and highlighting the pathway from discovery to clinical applications, healthcare and global health. We view translation broadly as the full spectrum of work that marks the pathway from discovery to global health, inclusive. The steps of translation that are within the scope of Translational Psychiatry include (i) fundamental discovery, (ii) bench to bedside, (iii) bedside to clinical applications (clinical trials), (iv) translation to policy and health care guidelines, (v) assessment of health policy and usage, and (vi) global health. All areas of medical research, including — but not restricted to — molecular biology, genetics, pharmacology, imaging and epidemiology are welcome as they contribute to enhance the field of translational psychiatry.
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