Bauer Helen Friedericke, Delling Jan Philipp, Bockmann Jürgen, Boeckers Tobias M, Schön Michael
Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany.
International Graduate School in Molecular Medicine Ulm, Ulm University, Ulm, Germany.
Front Behav Neurosci. 2023 Jan 9;16:1051175. doi: 10.3389/fnbeh.2022.1051175. eCollection 2022.
Individuals with a -related neurodevelopmental disorder, also termed Phelan-McDermid syndrome or abbreviated as PMS, exhibit significant global developmental delay, language impairment, and muscular hypotonia. Also common are repetitive behaviors and altered social interactions, in line with a diagnosis of autism spectrum disorders. This study investigated the developmental aspect of autism-related behaviors and other phenotypes in a -transgenic mouse model. The animals underwent two sets of identical behavioral experiments, spanning motor skills, social and repetitive behavior, and cognition: baseline began at 5 weeks of age, corresponding to human adolescence, and the follow-up was initiated when aged 13 weeks, resembling early adulthood in humans. Interestingly, the animals displayed relatively stable phenotypes. Moreover, motor coordination and endurance were impaired, while muscle strength was unchanged. Surprisingly, the animals displayed only minor impairments in social behavior, but pronounced stereotypic and repetitive behaviors. Some behavioral tests indicated increased avoidance and anxiety. While spatial learning and memory were unchanged, knockout animals displayed slightly impaired cognitive flexibility. Female animals had similar abnormalities as males in the paradigms testing avoidance, anxiety, and cognition, but were less pathological in motor function and repetitive behavior. In all test paradigms, heterozygous knockout animals had either no abnormal or a milder phenotype. Accurate characterization of animal models for genetic diseases is a prerequisite for understanding the pathophysiology. This is subsequently the basis for finding suitable and, ideally, translational biomarkers for therapeutic approaches and, thereby reducing the number of animals needed for preclinical trials.
患有与22q13.3相关的神经发育障碍（也称为费伦 - 麦克德米德综合征或简称为PMS）的个体表现出显著的全面发育迟缓、语言障碍和肌张力减退。重复行为和社交互动改变也很常见，符合自闭症谱系障碍的诊断。本研究在22q13.3转基因小鼠模型中调查了自闭症相关行为和其他表型的发育情况。这些动物接受了两组相同的行为实验，涵盖运动技能、社交和重复行为以及认知：基线实验从5周龄开始，相当于人类青春期，随访在13周龄时开始，类似于人类的成年早期。有趣的是，这些动物表现出相对稳定的表型。此外，运动协调和耐力受损，而肌肉力量未改变。令人惊讶的是，这些动物在社交行为方面仅表现出轻微损伤，但刻板和重复行为明显。一些行为测试表明回避和焦虑增加。虽然空间学习和记忆未改变，但基因敲除动物的认知灵活性略有受损。在测试回避、焦虑和认知的范式中，雌性动物与雄性动物有类似的异常，但在运动功能和重复行为方面病理程度较轻。在所有测试范式中，杂合基因敲除动物要么没有异常，要么表现出较轻的表型。准确表征遗传疾病的动物模型是理解病理生理学的先决条件。这随后是寻找适合且理想的治疗方法转化生物标志物的基础，从而减少临床前试验所需的动物数量。
