CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; IIIUC-Interdisciplinary Research Institute, University of Coimbra, 3030-789 Coimbra, Portugal.
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; Department of Life Sciences, University of Coimbra, 3004-517 Coimbra, Portugal.
Curr Opin Neurobiol. 2019 Aug;57:62-70. doi: 10.1016/j.conb.2019.01.004. Epub 2019 Feb 8.
Growing evidence implicates synaptic proteins in the pathogenesis of neuropsychiatric disorders such as autism spectrum disorder (ASD), intellectual disability (ID) and schizophrenia. In fact, mutations in genes encoding synaptic proteins are enriched and overlap among different conditions highlighting the complex and pleiotropic nature of these disorders. In this review, we discuss recently described candidate genes that affect excitatory synapse function and result in changes in spine number and morphology. Spine pathology has been observed in several animal models of disease and in human brain post-mortem samples from ID, ASD, and schizophrenia patients. Recent data point to convergent mechanisms, such as dysregulation of the actin cytoskeleton and dysfunction of microglia synaptic remodeling, underlying dendritic spine dysgenesis. Interestingly, the reversion of important pathologic features, including spine abnormalities, has been observed in adult animal models of neuropsychiatric disorders, suggesting that therapies may not be restricted to a specific developmental window. Shedding light on the specific mechanisms impacted in neuropsychiatric disorders will undeniably contribute to the development of more directed and personalized therapies.
越来越多的证据表明，突触蛋白与神经精神疾病的发病机制有关，如自闭症谱系障碍 (ASD)、智力障碍 (ID) 和精神分裂症。事实上，编码突触蛋白的基因突变在不同疾病中丰富且重叠，突出了这些疾病的复杂性和多效性。在这篇综述中，我们讨论了最近描述的影响兴奋性突触功能的候选基因，这些基因导致棘突数量和形态的变化。在几种疾病的动物模型以及 ID、ASD 和精神分裂症患者的人脑尸检样本中都观察到了脊柱病理学。最近的数据指出，树突棘发育不良的潜在机制是趋同的，如肌动蛋白细胞骨架的失调和小胶质细胞突触重塑的功能障碍。有趣的是，在神经精神疾病的成年动物模型中观察到了重要病理特征的逆转，包括棘突异常，这表明治疗方法可能不限于特定的发育窗口。阐明神经精神疾病中受影响的特定机制无疑将有助于开发更有针对性和个性化的治疗方法。
