Abellán-Álvaro Maria, Primo-Hernando Lidia, Martínez-Rodríguez Elena, Lanuza Enrique, Santos Mónica, Agustín-Pavón Carmen, Torres-Pérez Jose V
Department of Cellular Biology, Functional Biology and Physical Anthropology, University of Valencia, Burjassot, 46100, Valencia, Spain.
Unitat Predepartamental de Medicina, Universitat Jaume I, Castelló de La Plana, Spain.
Neuromolecular Med. 2025 Jun 17;27(1):46. doi: 10.1007/s12017-025-08867-9.
Rett syndrome (RTT), a severe neurodevelopmental disorder primarily affecting girls, is commonly caused by MECP2 loss-of-function mutations. Key symptoms include motor impairments, typical hand stereotypies and intellectual disability. Moreover, although not thoroughly studied, anxiety, heightened stress sensitivity, and aberrant pain perception are also an important component of the RTT phenotype. Emerging evidence suggests that early-life stress (ELS) worsens Mecp2-related phenotypic alterations in mice. Microglia, the resident immune cells within the central nervous system, play a critical role in RTT pathophysiology, yet the combined impact of ELS and Mecp2 deficiency on microglia has not been studied. Previously, we observed reduced activation of the periaqueductal grey (PAG, a cerebral structure involved in pain modulation, autonomic control, and defensive behaviours) in Mecp2-heterozygous (Mecp2-het) mice after thermal stimulation. Here, we investigated the impact of ELS on microglia morphology in the PAG under Mecp2 deficiency. To this end, we analysed microglia in the PAG of presymptomatic Mecp2-het mice previously subjected to maternal separation (MS) as a model of ELS, alongside corresponding control animals. Brain sections were immunolabelled for IBA1, a pan-microglial marker. Microglial cells within the PAG were evaluated for expression levels, morphological characteristics, and fractal properties. While global PAG analyses showed minimal differences, subdivision-specific analyses revealed significant microglial alterations. These findings suggest that ELS exacerbates Mecp2-related neurodevelopmental deficits, impairing microglia in a region-specific manner. Our data points to a microglial failure to morphologically adapt, rather than overt structural loss, in the PAG that may underlie some of the neurological dysfunctions observed in RTT.
雷特综合征（RTT）是一种主要影响女孩的严重神经发育障碍，通常由MECP2功能丧失突变引起。主要症状包括运动障碍、典型的手部刻板动作和智力残疾。此外，尽管尚未进行充分研究，但焦虑、高度的应激敏感性和异常的疼痛感知也是RTT表型的重要组成部分。新出现的证据表明，早期生活应激（ELS）会使小鼠中与Mecp2相关的表型改变恶化。小胶质细胞是中枢神经系统中的常驻免疫细胞，在RTT病理生理学中起关键作用，但ELS和Mecp2缺乏对小胶质细胞的综合影响尚未得到研究。此前，我们观察到热刺激后Mecp2杂合子（Mecp2-het）小鼠中脑导水管周围灰质（PAG，一种参与疼痛调节、自主控制和防御行为的脑结构）的激活减少。在此，我们研究了ELS对Mecp2缺乏情况下PAG中小胶质细胞形态的影响。为此，我们分析了先前作为ELS模型接受母体分离（MS）的症状前Mecp2-het小鼠PAG中的小胶质细胞，以及相应的对照动物。脑切片用泛小胶质细胞标记物IBA1进行免疫标记。评估PAG内小胶质细胞的表达水平、形态特征和分形特性。虽然对PAG的整体分析显示差异最小，但细分特异性分析揭示了明显的小胶质细胞改变。这些发现表明，ELS会加剧与Mecp2相关的神经发育缺陷，以区域特异性方式损害小胶质细胞。我们的数据表明，PAG中小胶质细胞在形态上无法适应，而非明显的结构丧失，这可能是RTT中观察到的一些神经功能障碍的基础。
