Wulaer B, Nagai T, Sobue A, Itoh N, Kuroda K, Kaibuchi K, Nabeshima T, Yamada K
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Genes Brain Behav. 2018 Nov;17(8):e12478. doi: 10.1111/gbb.12478. Epub 2018 Apr 30.
Disrupted-in-schizophrenia 1 (Disc1) is a key molecular driver for the biology of mental diseases. In order to investigate its role in brain function, we previously generated mice lacking exons 2 and 3 of Disc1 on a C57BL/6J genetic background (Disc1 mice), which have a deficiency of the full-length Disc1 protein. In the present study, we examined the role of Disc1 in cognitive function using a touchscreen-based visual discrimination (VD) task in which mice had to discriminate 1 of 2 stimuli simultaneously displayed on the screen and received a liquid reward. Disc1 mice showed impaired performance in the VD task, and this was mainly attributed to the perseverative response being significantly stronger than that in wild-type (WT) mice. Furthermore, the numbers of marbles buried in the marble burying test and nestlets shredded in the nestlet shredding test by Disc1 mice were significantly higher than those by WT mice, suggesting perseverative/compulsive behaviors by Disc1 mice. A treatment with clozapine ameliorated behavioral deficits in the VD and marble burying tasks. c-Fos expression was significantly stronger in the dorsomedial striatum (DMS), but not the dorsolateral striatum (DLS) after the first VD session in Disc1 mice than in WT mice. The treatment of mice that had previously expressed hM3Dq in the DMS with clozapine-N-oxide (CNO) impaired performance in the VD task. These results suggest that cognitive impairments accompanied by perseverative/compulsive behaviors in Disc1 mice are associated with hyperactivity of the DMS.
精神分裂症相关 1 基因（Disc1）是精神疾病生物学的关键分子驱动因素。为了研究其在脑功能中的作用，我们之前在 C57BL/6J 遗传背景下培育了缺失 Disc1 外显子 2 和 3 的小鼠（Disc1 小鼠），这些小鼠缺乏全长 Disc1 蛋白。在本研究中，我们使用基于触摸屏的视觉辨别（VD）任务来检测 Disc1 在认知功能中的作用，在该任务中，小鼠必须辨别同时显示在屏幕上的两种刺激中的一种，并获得液体奖励。Disc1 小鼠在 VD 任务中的表现受损，这主要归因于持续性反应比野生型（WT）小鼠明显更强。此外，Disc1 小鼠在大理石埋藏试验中埋藏的大理石数量和在碎巢试验中撕碎的巢材数量显著高于 WT 小鼠，表明 Disc1 小鼠存在持续性/强迫性行为。氯氮平治疗改善了 VD 和大理石埋藏任务中的行为缺陷。在第一次 VD 试验后，Disc1 小鼠背内侧纹状体（DMS）中的 c-Fos 表达明显强于 WT 小鼠，但背外侧纹状体（DLS）中并非如此。用氯氮平氮氧化物（CNO）治疗先前在 DMS 中表达 hM3Dq 的小鼠会损害其在 VD 任务中的表现。这些结果表明，Disc1 小鼠中伴有持续性/强迫性行为的认知障碍与 DMS 的过度活跃有关。
