■脆性X综合征(FXS),由于Fmr1基因的突变,是自闭症和遗传性智力障碍最常见的单基因原因。Fmr1编码脆性X信使核糖核蛋白(FMRP),它的缺失导致认知,情感,和与伏隔核(NAc)功能障碍相容的社会缺陷。这种结构在社会行为控制中至关重要,主要由多刺投射神经元(SPN)组成,通过多巴胺D1或D2受体表达来区分,连通性,和相关的行为功能。本研究旨在研究FMRP缺失如何差异影响SPN细胞特性,这对于对FXS细胞内表型进行分类至关重要。
■我们使用了一种新颖的Fmr1-/y::Drd1a-tdTomato小鼠模型,这允许在FXS小鼠中原位鉴定SPN亚型。使用RNA测序,成年雄性小鼠NAc的RNAScope和离体膜片钳,我们全面比较了SPN亚型的固有被动和主动特性。
■Fmr1转录本及其基因产物,FMRP,在两种SPN亚型中都有发现,指示Fmr1的潜在细胞特异性功能。研究发现,在Fmr1-/y::Drd1a-tdTomato小鼠中,通常将D1-与D2-SPN分开的独特膜特性和动作电位动力学在野生型小鼠中被逆转或废除。有趣的是,多变量分析通过公开区分野生型小鼠中每种细胞类型的表型性状在FXS中如何改变而强调了Fmr1消融的复合效应。
■我们的结果表明,FMRP的缺失破坏了表征NAcD1-和D2-SPN的标准二分法,导致同质表型。细胞性质的这种转变可能潜在地支持在FXS中观察到的病理学的选择方面。因此,了解FMRP缺失对SPN亚型的细微影响可以为FXS的病理生理学提供有价值的见解,为潜在的治疗策略开辟道路。
UNASSIGNED: Fragile X syndrome (FXS), resulting from a mutation in the Fmr1 gene, is the most common monogenic cause of autism and inherited intellectual disability. Fmr1 encodes the Fragile X Messenger Ribonucleoprotein (FMRP), and its absence leads to cognitive, emotional, and social deficits compatible with the nucleus
accumbens (NAc) dysfunction. This structure is pivotal in social behavior control, consisting mainly of spiny projection neurons (SPNs), distinguished by dopamine D1 or D2 receptor expression, connectivity, and associated behavioral functions. This study aims to examine how FMRP absence differentially affects SPN cellular properties, which is crucial for categorizing FXS cellular endophenotypes.
UNASSIGNED: We utilized a novel Fmr1-/y::Drd1a-tdTomato mouse model, which allows in-situ identification of SPN subtypes in FXS mice. Using RNA-sequencing, RNAScope and ex-vivo patch-clamp in adult male mice NAc, we comprehensively compared the intrinsic passive and active properties of SPN subtypes.
UNASSIGNED: Fmr1 transcripts and their gene product, FMRP, were found in both SPNs subtypes, indicating potential cell-specific functions for Fmr1. The study found that the distinguishing membrane properties and action potential kinetics typically separating D1- from D2-SPNs in wild-type mice were either reversed or abolished in Fmr1-/y::Drd1a-tdTomato mice. Interestingly, multivariate analysis highlighted the compound effects of Fmr1 ablation by disclosing how the phenotypic traits distinguishing each cell type in wild-type mice were altered in FXS.
UNASSIGNED: Our results suggest that the absence of FMRP disrupts the standard dichotomy characterizing NAc D1- and D2-SPNs, resulting in a homogenous phenotype. This shift in cellular properties could potentially underpin select aspects of the pathology observed in FXS. Therefore, understanding the nuanced effects of FMRP absence on SPN subtypes can offer valuable insights into the pathophysiology of FXS, opening avenues for potential therapeutic strategies.