National Center for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, 560065, India.
The University of Trans-Disciplinary Health Sciences and Technology, Bangalore, 560064, India.
Transl Psychiatry. 2021 Sep 25;11(1):494. doi: 10.1038/s41398-021-01618-x.
The schizophrenia-risk gene Tcf4 has been widely studied in the context of brain development using mouse models of haploinsufficiency, in utero knockdown and embryonic deletion. However, Tcf4 continues to be abundantly expressed in adult brain neurons where its functions remain unknown. Given the importance of Tcf4 in psychiatric diseases, we investigated its role in adult neurons using cell-specific deletion and genetic tracing in adult animals. Acute loss of Tcf4 in adult excitatory neurons in vivo caused hyperexcitability and increased dendritic complexity of neurons, effects that were distinct from previously observed effects in embryonic-deficiency models. Interestingly, transcriptomic analysis of genetically traced adult-deleted FACS-sorted Tcf4-knockout neurons revealed that Tcf4 targets in adult neurons are distinct from those in the embryonic brain. Meta-analysis of the adult-deleted neuronal transcriptome from our study with the existing datasets of embryonic Tcf4 deficiencies revealed plasma membrane and ciliary genes to underlie Tcf4-mediated structure-function regulation specifically in adult neurons. The profound changes both in the structure and excitability of adult neurons upon acute loss of Tcf4 indicates that proactive regulation of membrane-related processes underlies the functional and structural integrity of adult neurons. These findings not only provide insights for the functional relevance of continual expression of a psychiatric disease-risk gene in the adult brain but also identify previously unappreciated gene networks underpinning mature neuronal regulation during the adult lifespan.
精神分裂症风险基因 Tcf4 已在使用单倍体不足、宫内敲低和胚胎缺失的小鼠模型研究大脑发育方面得到广泛研究。然而，Tcf4 在成年大脑神经元中仍大量表达，其功能仍不清楚。鉴于 Tcf4 在精神疾病中的重要性，我们使用成年动物中的细胞特异性缺失和遗传追踪来研究其在成年神经元中的作用。体内急性缺失成年兴奋性神经元中的 Tcf4 会导致神经元过度兴奋和树突复杂性增加，这些效应与以前在胚胎缺陷模型中观察到的效应不同。有趣的是，对遗传追踪的成年缺失 FACS 分选 Tcf4 敲除神经元进行的转录组分析表明，成年神经元中的 Tcf4 靶标与胚胎大脑中的靶标不同。对我们的研究中成年缺失神经元转录组与现有的胚胎 Tcf4 缺陷数据集进行的荟萃分析显示，质膜和纤毛基因是 Tcf4 介导的结构-功能调节的基础，特别是在成年神经元中。Tcf4 的急性缺失不仅会导致成年神经元的结构和兴奋性发生深刻变化，还表明主动调节与膜相关的过程是成年神经元功能和结构完整性的基础。这些发现不仅为精神疾病风险基因在成年大脑中的持续表达的功能相关性提供了深入了解，还确定了以前未被重视的成熟神经元在成年期调节的基因网络。
