Center for Behavioral Neuroscience, Institute of Experimental Psychology, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, USA.
Neuroscience. 2022 Jun 15;493:41-51. doi: 10.1016/j.neuroscience.2022.04.013. Epub 2022 Apr 21.
Alterations in cognitive functions, social behaviors and stress reactions are commonly diagnosed in chronic mental illnesses (CMI). Animal models expressing mutant genes associated to CMI represent either rare mutations or those contributing only minimally to genetic risk. Non-genetic causes of CMI can be modeled by disturbing downstream signaling pathways, for example by inducing protein misassembly or aggregation. The Disrupted-in-Schizophrenia 1 (DISC1) gene was identified to be disrupted and thereby haploinsufficient in a large pedigree where it was associated with CMI. In a subset of CMI patients, the DISC1 protein misassembles to an insoluble protein. This has been modeled in a rat (tgDISC1 rat) where the full-length, non mutant human transgene was overexpressed and cognitive impairments were observed. Here, we investigated the scope of effects of DISC1 protein misassembly by investigating spatial memory, social behavior and stress resilience. In water maze tasks, the tgDISC1 rats showed intact spatial learning and memory, but were deficient in flexible adaptation to spatial reversal learning compared to littermate controls. They also displayed less social interaction. Additionally, there was a trend towards increased corticosterone levels after restraint stress in the tgDISC1 rats. Our findings suggest that DISC1 protein misassembly leads to disturbances of cognitive flexibility and social behaviors, and might also be involved in stress sensitization. Since the observed behavioral features resemble symptoms of CMI, the tgDISC1 rat may be a valuable model for the investigation of cognitive, social and - possibly - also stress-related symptoms of major mental illnesses.
认知功能、社交行为和应激反应的改变在慢性精神疾病（CMI）中经常被诊断出来。表达与 CMI 相关的突变基因的动物模型要么代表罕见的突变，要么只对遗传风险有微小的贡献。CMI 的非遗传原因可以通过干扰下游信号通路来建模，例如通过诱导蛋白质错误组装或聚集。Disrupted-in-Schizophrenia 1 (DISC1) 基因在一个与 CMI 相关的大型家系中被发现缺失和杂合不足。在 CMI 患者的亚组中，DISC1 蛋白错误组装成不可溶的蛋白质。在一种大鼠（tgDISC1 大鼠）中已经建立了这种模型，其中全长、非突变的人类转基因过度表达，并观察到认知障碍。在这里，我们通过研究空间记忆、社交行为和应激弹性来研究 DISC1 蛋白错误组装的影响范围。在水迷宫任务中，tgDISC1 大鼠表现出完整的空间学习和记忆，但与同窝对照相比，在空间反转学习的灵活适应方面存在缺陷。它们的社交互动也较少。此外，tgDISC1 大鼠在束缚应激后皮质酮水平有升高的趋势。我们的研究结果表明，DISC1 蛋白错误组装导致认知灵活性和社交行为障碍，并且可能还与应激敏感化有关。由于观察到的行为特征类似于 CMI 的症状，tgDISC1 大鼠可能是研究重大精神疾病认知、社交和 - 可能 - 应激相关症状的有价值的模型。
