Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Nat Neurosci. 2011 Mar;14(3):285-93. doi: 10.1038/nn.2741.
Substantial progress has been made toward understanding the genetic architecture, cellular substrates, brain circuits and endophenotypic profiles of neuropsychiatric disorders, including autism spectrum disorders (ASD), schizophrenia and Alzheimer's disease. Recent evidence implicates spiny synapses as important substrates of pathogenesis in these disorders. Although synaptic perturbations are not the only alterations relevant for these diseases, understanding the molecular underpinnings of spine pathology may provide insight into their etiologies and may reveal new drug targets. Here we discuss recent neuropathological, genetic, molecular and animal model studies that implicate structural alterations at spiny synapses in the pathogenesis of major neurological disorders, focusing on ASD, schizophrenia and Alzheimer's disease as representatives of these categories across different ages of onset. We stress the importance of reverse translation, collaborative and multidisciplinary approaches, and the study of the spatio-temporal roles of disease molecules in the context of synaptic regulatory pathways and neuronal circuits that underlie disease endophenotypes.
在理解神经精神疾病（包括自闭症谱系障碍（ASD）、精神分裂症和阿尔茨海默病）的遗传结构、细胞基础、大脑回路和表型特征方面已经取得了重大进展。最近的证据表明棘突突触是这些疾病发病机制的重要底物。尽管突触扰动不是这些疾病唯一相关的改变，但了解脊柱病理学的分子基础可能有助于深入了解其病因，并可能揭示新的药物靶点。在这里，我们讨论了最近的神经病理学、遗传学、分子和动物模型研究，这些研究表明棘突突触的结构改变与主要神经精神疾病的发病机制有关，重点关注 ASD、精神分裂症和阿尔茨海默病，这些疾病在不同发病年龄代表了这些类别。我们强调了反向翻译、协作和多学科方法的重要性，以及在疾病分子的时空作用方面的研究，这些研究与突触调节途径和神经元回路有关，而这些途径和回路是疾病表型的基础。
