Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA.
California National Primate Research Center, University of California, Davis, Davis, CA 95616, USA.
Sci Transl Med. 2018 May 2;10(439). doi: 10.1126/scitranslmed.aam9100.
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by core social impairments. ASD remains poorly understood because of the difficulty in studying disease biology directly in patients and the reliance on mouse models that lack clinically relevant, complex social cognition abilities. We use ethological observations in rhesus macaques to identify male monkeys with naturally occurring low sociality. These monkeys showed differences in specific neuropeptide and kinase signaling pathways compared to socially competent male monkeys. Using a discovery and replication design, we identified arginine vasopressin (AVP) in cerebrospinal fluid (CSF) as a key marker of group differences in monkey sociality; we replicated these findings in an independent monkey cohort. We also confirmed in an additional monkey cohort that AVP concentration in CSF is a stable trait-like measure. Next, we showed in a small pediatric cohort that CSF AVP concentrations were lower in male children with ASD compared to age-matched male children without ASD (but with other medical conditions). We demonstrated that CSF AVP concentration was sufficient to accurately distinguish ASD cases from medical controls. These data suggest that AVP and its signaling pathway warrant consideration in future research studies investigating new targets for diagnostics and drug development in ASD.
自闭症谱系障碍（ASD）是一种神经发育障碍，其特征是核心社交障碍。由于难以直接在患者中研究疾病生物学，并且依赖于缺乏临床相关的复杂社交认知能力的小鼠模型，因此 ASD 仍未得到充分理解。我们使用恒河猴的行为观察来识别自然社交能力低下的雄性猴子。与社交能力强的雄性猴子相比，这些猴子在特定神经肽和激酶信号通路中表现出差异。使用发现和复制设计，我们确定脑脊液（CSF）中的精氨酸加压素（AVP）是猴子社交性群体差异的关键标志物；我们在一个独立的猴子队列中复制了这些发现。我们还在另一个猴子队列中证实，CSF 中的 AVP 浓度是一种稳定的特质样测量。接下来，我们在一个小的儿科队列中表明，与年龄匹配的无 ASD（但有其他医疗条件）的男性儿童相比，患有 ASD 的男性儿童的 CSF AVP 浓度较低。我们证明 CSF AVP 浓度足以准确区分 ASD 病例和医学对照。这些数据表明，AVP 及其信号通路值得在未来的研究中考虑，以寻找 ASD 诊断和药物开发的新靶点。
