精神病风险基因转录因子4 (TCF4) 调节不同抑制性内部神经元亚型的密度和连接性
Huei-Ying Chen1, BaDoi N Phan2,3,4, Gina Shim1
1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, 21205, USA.
Molecular psychiatry
|September 28, 2023
概括
转录因子4 (TCF4) 对于GABA活性内部神经元发育至关重要. TCF4中的突变会破坏特定的内部神经元群体,影响大脑电路,并导致皮特-霍普金斯综合征的病理生理学.
科学领域:
- 神经科学是一个神经科学.
- 遗传学 是一个遗传学.
- 发展生物学 发展生物学
背景情况:
- 转录因子4 (TCF4) 与自闭症谱系障碍 (ASD) 等精神疾病有关.
- 自体主导的TCF4突变导致皮特-霍普金斯综合征 (PTHS),这是ASD的一种形式.
- 在GABAergic内部神经元 (INs) 中,TCF4的表达很高,这表明它在神经元功能中的作用.
研究的目的:
- 为了研究TCF4在PTHS的小鼠模型中GABAergic内部神经元的发展和功能中的作用.
- 为了确定受TCF4突变影响的特定内部神经元群体.
- 了解TCF4功能障碍对神经电路的下游后果.
主要方法:
- 细胞类型特异表达分析 (CSEA) 和细胞解卷 (CD) 在PTHS小鼠模型中的大量RNA测序数据上.
- 在Tcf4+/tr小鼠中对亚型特定的IN标记物的免疫组织化学 (IHC) 分析.
- 对记者小鼠进行分析,以量化特定的IN种群.
主要成果:
- 在PTHS模型中差异表达的基因被丰富为表达帕瓦胺 (PV+) 的INs.
- 细胞解体预测PV + INs的减少.
- TCF4缺乏导致皮质中的PV+,血管活性肠 (VIP+),皮质皮质中的皮质素 (CST+) INs和条形体中的胆固醇 (ChAT+) INs减少.
- 索马托斯塔丁 (SST+) INs没有受到影响.
- 特定IN群体的减少改变了皮层神经元上的刺激/抑制平衡.
结论:
- TCF4对于特定的GABAergic内部神经元亚型的正常发育至关重要.
- 这些IN种群的失调有助于PTHS的病理生理学.
- 抑制神经网络是PTHS中受TCF4突变影响的关键区域.
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