Ludwig Maximillian's University, Department of Psychiatry, Laboratory of Molecular Neurobiology, Munich, Germany.
Max Planck Institute of Experimental Medicine, Department of Neurogenetics, Göttingen, Germany.
Transl Psychiatry. 2020 Oct 9;10(1):343. doi: 10.1038/s41398-020-01026-7.
The transcription factor TCF4 was confirmed in several large genome-wide association studies as one of the most significant schizophrenia (SZ) susceptibility genes. Transgenic mice moderately overexpressing Tcf4 in forebrain (Tcf4tg) display deficits in fear memory and sensorimotor gating. As second hit, we exposed Tcf4tg animals to isolation rearing (IR), chronic social defeat (SD), enriched environment (EE), or handling control (HC) conditions and examined mice with heterozygous deletion of the exon 4 (Tcf4Ex4δ) to unravel gene-dosage effects. We applied multivariate statistics for behavioral profiling and demonstrate that IR and SD cause strong cognitive deficits of Tcf4tg mice, whereas EE masked the genetic vulnerability. We observed enhanced long-term depression in Tcf4tg mice and enhanced long-term potentiation in Tcf4Ex4δ mice indicating specific gene-dosage effects. Tcf4tg mice showed higher density of immature spines during development as assessed by STED nanoscopy and proteomic analyses of synaptosomes revealed concurrently increased levels of proteins involved in synaptic function and metabolic pathways. We conclude that environmental stress and Tcf4 misexpression precipitate cognitive deficits in 2-hit mouse models of relevance for schizophrenia.
转录因子 TCF4 在几项大型全基因组关联研究中被确认为精神分裂症（SZ）最显著的易感基因之一。在前脑中度过表达 Tcf4 的转基因小鼠表现出恐惧记忆和感觉运动门控缺陷。作为第二次打击，我们将 Tcf4tg 动物暴露于隔离饲养（IR）、慢性社会挫败（SD）、丰富环境（EE）或处理对照（HC）条件下，并检查具有外显子 4 缺失（Tcf4Ex4δ）的杂合子的小鼠，以揭示基因剂量效应。我们应用多元统计学进行行为分析，并证明 IR 和 SD 导致 Tcf4tg 小鼠认知功能严重受损，而 EE 掩盖了遗传脆弱性。我们观察到 Tcf4tg 小鼠的长时程抑郁增强，而 Tcf4Ex4δ 小鼠的长时程增强增强，表明存在特定的基因剂量效应。通过 STED 纳米显微镜评估，Tcf4tg 小鼠在发育过程中表现出更高密度的不成熟棘突，突触体的蛋白质组学分析显示参与突触功能和代谢途径的蛋白质水平同时升高。我们得出结论，环境应激和 Tcf4 表达错误导致与精神分裂症相关的 2 击小鼠模型认知功能障碍。
