PDF(Pubmed)
Abstract：
Mutations in the activity-dependent transcription factor MEF2C have been associated with several neuropsychiatric disorders. Among these, autism spectrum disorder (ASD)-related behavioral deficits are manifested. Multiple animal models that harbor mutations in Mef2c have provided compelling evidence that Mef2c is indeed an ASD gene. However, studies in mice with germline or global brain knock-out of Mef2c are limited in their ability to identify the precise neural substrates and cell types that are required for the expression of Mef2c-mediated ASD behaviors. Given the role of hippocampal neurogenesis in cognitive and social behaviors, in this study we aimed to investigate the role of Mef2c in the structure and function of newly generated dentate granule cells (DGCs) in the postnatal hippocampus and to determine whether disrupted Mef2c function is responsible for manifesting ASD behaviors. Overexpression of Mef2c (Mef2cOE ) arrested the transition of neurogenesis at progenitor stages, as indicated by sustained expression of Sox2+ in Mef2cOE DGCs. Conditional knock-out of Mef2c (Mef2ccko ) allowed neuronal commitment of Mef2ccko cells; however, Mef2ccko impaired not only dendritic arborization and spine formation but also synaptic transmission onto Mef2ccko DGCs. Moreover, the abnormal structure and function of Mef2ccko DGCs led to deficits in social interaction and social novelty recognition, which are key characteristics of ASD behaviors. Thus, our study revealed a dose-dependent requirement of Mef2c in the control of distinct steps of neurogenesis, as well as a critical cell-autonomous function of Mef2c in newborn DGCs in the expression of proper social behavior in both sexes.
摘要：
活性依赖性转录因子MEF2C的突变与几种神经精神疾病有关。其中,自闭症谱系障碍（ASD）相关的行为缺陷表现出来。在Mef2c中含有突变的多个动物模型提供了令人信服的证据，证明Mef2c确实是ASD基因。然而,对Mef2c种系或全脑敲除的小鼠的研究在识别表达Mef2c介导的ASD行为所需的精确神经底物和细胞类型的能力方面受到限制。鉴于海马神经发生在认知和社会行为中的作用，在这项研究中，我们旨在研究Mef2c在出生后海马新生齿状颗粒细胞（DGC）的结构和功能中的作用，并确定是否破坏的Mef2c功能负责表现ASD行为。Mef2c（Mef2cOE）的过表达在祖细胞阶段阻止了神经发生的转变，如Mef2cOEDGC中Sox2+的持续表达所示。Mef2c（Mef2ccko）的条件敲除允许Mef2ccko细胞的神经元承诺；然而，Mef2ccko不仅损害了树突状乔木和脊柱形成，还有突触传递到Mef2cckoDGC上。此外，Mef2cckoDGC的结构和功能异常导致了社会互动和社会新颖性识别的缺陷，这是ASD行为的关键特征。因此，我们的研究揭示了Mef2c在控制神经发生的不同步骤中的剂量依赖性需求，以及Mef2c在新生儿DGC中在表达两性适当的社会行为方面的关键细胞自主功能。重要性声明自闭症谱系障碍（ASD）是一种神经发育障碍，世界各地儿童的沟通和行为缺陷。与ASD相关的遗传复杂性和异质性阻碍了该领域建立与ASD相关的任何精确的细胞底物。最近的研究表明海马神经发生是社会行为和ASD样行为的关键参与者之一。这里,使用转录因子Mef2c的条件缺失，在海马新生神经元或abDGC中，我们已经证明了Mef2c如何通过调节结构发展来影响行为，生理学,和abDGC的功能。我们的结果揭示了Mef2c在神经发生中的重要作用，并将海马神经发生确定为社会行为所必需的神经底物。
