Max-Planck-Institute of Experimental Medicine, Research Group Gene Expression and Signaling, Hermann-Rein-Str. 3, 37075 Göttingen, Germany.
Behav Brain Res. 2013 Jan 15;237:348-56. doi: 10.1016/j.bbr.2012.10.001. Epub 2012 Oct 13.
The basic helix-loop-helix (bHLH) transcription factor TCF4 was confirmed in the combined analysis of several large genome-wide association studies (GWAS) as one of the rare highly replicated significant schizophrenia (SZ) susceptibility genes in large case-control cohorts. Focused genetic association studies showed that TCF4 influences verbal learning and memory, and modulates sensorimotor gating. Mice overexpressing Tcf4 in the forebrain (Tcf4tg) display cognitive deficits in hippocampus-dependent learning tasks and impairment of prepulse inhibition, a well-established endophenotype of SZ. The spectrum of cognitive deficits in SZ subjects, however, is broad and covers attention, working memory, and anticipation. Collectively, these higher order cognitive processes and the recall of remote memories are thought to depend mainly on prefrontal cortical networks. To further investigate cognitive disturbances in Tcf4tg mice, we employed the trace fear conditioning paradigm that requires attention and critically depends on the anterior cingulate cortex (ACC). We show that Tcf4tg mice display deficits in recent and remote trace fear memory and are impaired at anticipating aversive stimuli. We also assessed mRNA expression of the neuronal activity-regulated gene Fos in the ACC and hippocampus. Upon trace conditioning, Fos expression is reduced in Tcf4tg mice as compared to controls, which parallels cognitive impairments in this learning paradigm. Collectively, these data indicate that the reduced cognitive performance in Tcf4tg mice includes deficits at the level of attention and behavioral anticipation.
基本螺旋-环-螺旋（bHLH）转录因子 TCF4 在几项大型全基因组关联研究（GWAS）的综合分析中被证实是大型病例对照队列中罕见的高度复制的显著精神分裂症（SZ）易感性基因之一。集中的遗传关联研究表明 TCF4 影响语言学习和记忆，并调节感觉运动门控。在前脑过度表达 Tcf4 的小鼠（Tcf4tg）在海马依赖学习任务中表现出认知缺陷，并损害了 PPI，这是 SZ 的一个既定的内表型。然而，SZ 受试者的认知缺陷范围很广，包括注意力、工作记忆和预期。总的来说，这些更高阶的认知过程和对远程记忆的回忆主要依赖于前额叶皮质网络。为了进一步研究 Tcf4tg 小鼠的认知障碍，我们采用了痕迹恐惧条件反射范式，该范式需要注意力，并严重依赖前扣带皮层（ACC）。我们表明 Tcf4tg 小鼠在近期和远程痕迹恐惧记忆中存在缺陷，并且在预期厌恶刺激时存在障碍。我们还评估了 ACC 和海马体中神经元活性调节基因 Fos 的 mRNA 表达。在痕迹条件反射后，与对照组相比，Tcf4tg 小鼠中的 Fos 表达减少，这与该学习范式中的认知障碍相平行。总的来说，这些数据表明 Tcf4tg 小鼠的认知表现下降包括注意力和行为预期水平的缺陷。
