Mice with exonic RELN deletion identified from a patient with schizophrenia have impaired visual discrimination learning and reversal learning in touchscreen operant tasks
Mice with exonic RELN deletion identified from a patient with schizophrenia have impaired visual discrimination learning and reversal learning in touchscreen operant tasks
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DOI：
10.1016/j.bbr.2021.113569
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发表时间：
2021-09
影响因子：
2.7
通讯作者：
Jingzhu Liao;Geyao Dong;Bolati Wulaer;Masahito Sawahata;H. Mizoguchi;D. Mori;N. Ozaki;T. Nabeshima;T. Nagai;Kiyofumi Yamada
中科院分区：
文献类型：
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作者：
Jingzhu Liao;Geyao Dong;Bolati Wulaer;Masahito Sawahata;H. Mizoguchi;D. Mori;N. Ozaki;T. Nabeshima;T. Nagai;Kiyofumi Yamada
Reelin基因（Reelin gene，CRN）编码一种大的细胞外蛋白，在大脑发育和成年大脑功能中具有多种作用。它激活成人大脑中一系列神经元信号转导通路，这些通路在突触可塑性、树突形态和认知功能中起作用。为了进一步研究Relnin在脑功能中的作用，我们使用C57 BL/6 J品系产生了一个小鼠品系，该品系具有从日本精神分裂症患者中鉴定的特异性Reln缺失（Reln-del小鼠）。这些小鼠表现出异常的社会性，但Reln缺失对高级脑功能（如学习和行为灵活性）的病理生理学意义仍不清楚。在这项研究中，使用基于触摸屏的视觉辨别（VD）和逆转学习（RL）任务评估了Reln-del小鼠的认知功能。与野生型（WT）同窝小鼠相比，Reln-del小鼠在简单VD任务中表现出正常的学习，但在复杂VD任务中学习延迟。在RL任务中，学习阶段分为早期持续阶段（正确率<50%）和后期学习阶段（正确率≥50%），与WT小鼠相比，Reln-del小鼠在简单RL和复杂RL任务中表现出正常的持续能力，但再学习能力受损。这些结果表明，Reln-del小鼠的学习能力受损，但行为灵活性不受影响。总之，在Reln-del小鼠中观察到的行为异常表明，该小鼠模型是一种有用的临床前工具，用于研究精神分裂症认知障碍的神经生物学机制和治疗策略。
The Reelin gene (RELN) encodes a large extracellular protein, which has multiple roles in brain development and adult brain function. It activates a series of neuronal signal transduction pathways in the adult brain that function in synaptic plasticity, dendritic morphology, and cognitive function. To further investigate the roles ofRelnin brain function, we generated a mouse line using the C57BL/6 J strain with the specificRelndeletion identified from a Japanese patient with schizophrenia (Reln-del mice). These mice exhibited abnormal sociality, but the pathophysiological significance of theRelndeletion for higher brain functions, such as learning and behavioral flexibility remains unclear. In this study, cognitive function inReln-del mice was assessed using touchscreen-based visual discrimination (VD) and reversal learning (RL) tasks.Reln-del mice showed normal learning in the simple VD task, but the learning was delayed in the complex VD task as compared to their wild-type (WT) littermates. In the RL task, sessions were divided into early perseverative phase (sessions with <50% correct) and later learning phase (sessions with ≥50% correct).Reln-del mice showed normal perseveration but impaired relearning ability in both simple RL and complex RL task as compared to WT mice. These results suggest thatReln-del mice have impaired learning ability, but the behavioral flexibility is unaffected. Overall, the observed behavioral abnormalities inReln-del mice suggest that this mouse model is a useful preclinical tool for investigating the neurobiological mechanism underlying cognitive impairments in schizophrenia and a therapeutic strategy.