Hadjas Lotfi C, Schartner Michael M, Cand Jennifer, Creed Meaghan C, Pascoli Vincent, Lüscher Christian, Simmler Linda D
Department of Basic Neurosciences, University of Geneva, Rue Michel-Servet 1, 1206, Geneva, Switzerland.
Service de Neurologie, Department of Clinical Neurosciences, Geneva University Hospital, Rue Gabrielle-Perret-Gentil 4, 1205, Geneva, Switzerland.
Neuropsychopharmacology. 2020 Nov;45(12):2020-2029. doi: 10.1038/s41386-020-0747-3. Epub 2020 Jun 25.
Obsessive-compulsive disorder (OCD) is a circuit disorder involving corticostriatal projections, which play a role in motor control. The Sapap3-knockout (KO) mouse is a mouse model to study OCD and recapitulates OCD-like compulsion through excessive grooming behavior, with skin lesions appearing at advanced age. Deficits in corticostriatal control provide a link to the pathophysiology of OCD. However, there remain significant gaps in the characterization of the Sapap3-KO mouse, with respect to age, specificity of synaptic dysfunction, and locomotor phenotype. We therefore investigated the corticostriatal synaptic phenotype of Sapap3-KO mice using patch-clamp slice electrophysiology, in adult mice and with projection specificity. We also analyzed grooming across age and locomotor phenotype with a novel, unsupervised machine learning technique (MoSeq). Increased grooming in Sapap3-KO mice without skin lesions was age independent. Synaptic deficits persisted in adulthood and involved the projections from the motor cortices and cingulate cortex to the dorsolateral and dorsomedial striatum. Decreased synaptic strength was evident at the input from the primary motor cortex by reduction in AMPA receptor function. Hypolocomotion, i.e., slowness of movement, was consistently observed in Sapap3-KO mice. Our findings emphasize the utility of young adult Sapap3-KO mice to investigate corticostriatal synaptic dysfunction in motor control.
强迫症（OCD）是一种涉及皮质纹状体投射的环路障碍，皮质纹状体投射在运动控制中发挥作用。Sapap3基因敲除（KO）小鼠是一种用于研究强迫症的小鼠模型，通过过度梳理行为重现类似强迫症的强迫行为，在老年时会出现皮肤损伤。皮质纹状体控制缺陷为强迫症的病理生理学提供了联系。然而，在Sapap3-KO小鼠的特征描述方面，在年龄、突触功能障碍的特异性和运动表型方面仍存在重大差距。因此，我们使用膜片钳切片电生理学方法，在成年小鼠中并具有投射特异性，研究了Sapap3-KO小鼠的皮质纹状体突触表型。我们还使用一种新颖的无监督机器学习技术（MoSeq）分析了不同年龄和运动表型的梳理行为。没有皮肤损伤的Sapap3-KO小鼠梳理行为增加与年龄无关。突触缺陷在成年期持续存在，涉及从运动皮质和扣带回皮质到背外侧和背内侧纹状体的投射。通过AMPA受体功能降低，初级运动皮质输入处的突触强度明显降低。在Sapap3-KO小鼠中始终观察到运动迟缓，即运动缓慢。我们的研究结果强调了年轻成年Sapap3-KO小鼠在研究运动控制中皮质纹状体突触功能障碍方面的实用性。
