Center for Neurobehavioral Genetics, Semel Institute for Neuroscience & Human Behavior, Department of Psychiatry & Biobehavioral Sciences, Brain Research Institute, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.
Curr Opin Neurol. 2011 Apr;24(2):114-8. doi: 10.1097/WCO.0b013e32834451fb.
This article reviews recent literature describing novel mouse genetic models of obsessive-compulsive disorder-like behaviors and neurobiological insights gained from analyses of such models.
Obsessive-compulsive disorder is a common neuropsychiatric disorder characterized by recurrent intrusive thoughts (obsessions) and ritualistic (compulsive) behaviors. Although the cause of this disorder remains unclear, recent studies of novel mouse genetic models with excessive grooming behaviors have begun to shed light on the molecular and cellular mechanisms underlying the pathogenesis of 'obsessive-compulsive disorder-like' behaviors. Genetic deletion of three genes in mice, Hoxb8, Sapap3, and Slitrk5, leads to pathological behaviors including adult-onset excessive grooming with mild-to-severe hair loss and self-injury. In two of the models, the Sapap3-deficient and the Slitrk5-deficient mice, the abnormal grooming behaviors are associated with enhanced anxiety and these pathological behaviors can be curtailed with subchronic administration of a selective serotonin reuptake inhibitor, suggesting the predictive validity of such models. Molecular, pathophysiological, and genetic analyses of these models reveal several insights on the etiological basis of abnormal behaviors in these mice, including abnormal cortico-striatal synapse formation and function in Sapap3 mice, impaired development and function of bone marrow-derived microglia in Hoxb8 mice, and abnormal striatal neuronal differentiation and neurotransmission in Slitrk5 mice.
Novel animal models provide powerful tools to investigate the molecular, cellular, and circuitry mechanisms of obsessive-compulsive disorder-like behaviors. Detailed analyses of these models may provide candidate molecules and mechanisms for the investigation of cause and therapy of obsessive-compulsive disorder.
本文综述了最近描述类似强迫症行为的新型小鼠遗传模型的文献，并从这些模型的分析中获得了神经生物学见解。
强迫症是一种常见的神经精神疾病，其特征是反复出现的侵入性思维（强迫症）和仪式性（强迫性）行为。尽管这种疾病的原因尚不清楚，但最近对过度梳理行为的新型小鼠遗传模型的研究开始揭示“强迫症样”行为发病机制的分子和细胞机制。在小鼠中敲除三个基因（Hoxb8、Sapap3 和 Slitrk5）会导致病理性行为，包括成年后过度梳理，伴有轻度至重度脱发和自残。在其中两种模型中，Sapap3 缺陷型和 Slitrk5 缺陷型小鼠异常梳理行为与焦虑增强有关，这些病理性行为可以通过亚慢性给予选择性 5-羟色胺再摄取抑制剂来抑制，表明这些模型具有预测性。对这些模型的分子、病理生理学和遗传学分析揭示了这些小鼠异常行为的病因基础的几个见解，包括 Sapap3 小鼠皮质纹状体突触形成和功能异常、Hoxb8 小鼠骨髓源性小胶质细胞发育和功能受损以及 Slitrk5 小鼠纹状体神经元分化和神经传递异常。
新型动物模型为研究强迫症样行为的分子、细胞和电路机制提供了有力工具。对这些模型的详细分析可能为强迫症的病因和治疗研究提供候选分子和机制。
