Siqueiros-Sanchez Monica, Serur Yaffa, McGhee Chloe A, Smith Taylor F, Green Tamar
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California; Division of Interdisciplinary Brain Sciences, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California.
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California; Division of Interdisciplinary Brain Sciences, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California.
Biol Psychiatry. 2025 Mar 1;97(5):461-498. doi: 10.1016/j.biopsych.2024.09.019. Epub 2024 Oct 2.
Neurofibromatosis type 1 (NF1) and Noonan syndrome (NS) are neurogenetic syndromes caused by pathogenetic variants encoding components of the Ras-ERK-MAPK (Ras/extracellular signal-regulated kinase/mitogen-activated protein kinase) signaling pathway (Ras pathway). NF1 and NS are associated with differences in social communication and related neuropsychiatric risks. During the last decade, there has been growing interest in Ras-linked syndromes as models to understand social communication deficits and autism spectrum disorder. We systematically review the literature between 2010 and 2023 focusing on the social communication construct of the Research Domain Criteria framework. We provide an integrative summary of the research on facial and nonfacial social communication processes in NF1 and NS across molecular, cellular, neural circuitry, and behavioral domains. At the molecular and cellular levels, dysregulation in the Ras pathway is intricately tied to variations in social communication through changes in GABAergic (gamma-aminobutyric acidergic), glutamatergic, and serotonergic transmission, as well as inhibitory/excitatory imbalance. Neural circuitry typically associated with learning, attention, and memory in NF1 and NS (e.g., corticostriatal connectivity) is also implicated in social communication. We highlight less-researched potential mechanisms for social communication, such as white matter connectivity and the default mode network. Finally, key gaps in NF1 and NS literature are identified, and a roadmap for future research is provided. By leveraging genetic syndrome research, we can understand the mechanisms associated with behaviors and psychiatric disorders.
1型神经纤维瘤病（NF1）和努南综合征（NS）是由编码Ras-ERK-MAPK（Ras/细胞外信号调节激酶/丝裂原活化蛋白激酶）信号通路（Ras通路）成分的致病变异引起的神经遗传综合征。NF1和NS与社会交往差异及相关神经精神风险有关。在过去十年中，作为理解社会交往缺陷和自闭症谱系障碍的模型，与Ras相关的综合征越来越受到关注。我们系统回顾了2010年至2023年期间的文献，重点关注研究领域标准框架中的社会交往结构。我们对NF1和NS在分子、细胞、神经回路和行为领域的面部和非面部社会交往过程的研究进行了综合总结。在分子和细胞水平上，Ras通路的失调通过GABA能（γ-氨基丁酸能）、谷氨酸能和5-羟色胺能传递的变化以及抑制/兴奋失衡，与社会交往的变化密切相关。NF1和NS中通常与学习、注意力和记忆相关的神经回路（如皮质纹状体连接）也与社会交往有关。我们强调了社会交往中研究较少的潜在机制，如白质连接和默认模式网络。最后，我们确定了NF1和NS文献中的关键空白，并提供了未来研究的路线图。通过利用遗传综合征研究，我们可以了解与行为和精神障碍相关的机制。
