Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium.
Department of Fundamental Neuroscience, University of Lausanne, 1005 Lausanne, Switzerland; email:
Annu Rev Genomics Hum Genet. 2017 Aug 31;18:115-142. doi: 10.1146/annurev-genom-091416-035332.
The Ras-MAPK and PI3K-AKT-mTOR signaling cascades were originally identified as cancer regulatory pathways but have now been demonstrated to be critical for synaptic plasticity and behavior. Neurodevelopmental disorders arising from mutations in these pathways exhibit related neurological phenotypes, including cognitive dysfunction, autism, and intellectual disability. The downstream targets of these pathways include regulation of transcription and protein synthesis. Other disorders that affect protein translation include fragile X syndrome (an important cause of syndromal autism), and other translational regulators are now also linked to autism. Here, we review how mechanisms of synaptic plasticity have been revealed by studies of mouse models for Ras-MAPK, PI3K-AKT-mTOR, and translation regulatory pathway disorders. We discuss the face validity of these mouse models and review current progress in clinical trials directed at ameliorating cognitive and behavioral symptoms.
Ras-MAPK 和 PI3K-AKT-mTOR 信号级联最初被确定为癌症调控途径，但现在已被证明对突触可塑性和行为至关重要。这些途径中的突变引起的神经发育障碍表现出相关的神经表型，包括认知功能障碍、自闭症和智力障碍。这些途径的下游靶标包括转录和蛋白质合成的调节。影响蛋白质翻译的其他疾病包括脆性 X 综合征（综合征性自闭症的重要原因），现在其他翻译调节剂也与自闭症有关。在这里，我们回顾了 Ras-MAPK、PI3K-AKT-mTOR 和翻译调节途径障碍的小鼠模型研究如何揭示突触可塑性的机制。我们讨论了这些小鼠模型的表面有效性，并回顾了针对改善认知和行为症状的临床试验的最新进展。
