The fragile X mental retardation protein (FMRP), an RNA-binding protein that mediates the transport, stability, and translation of hundreds of brain RNAs, is critically involved in regulating synaptic function. Loss of FMRP, as in fragile X syndrome (FXS), is a leading monogenic cause of autism and results in altered structural and functional synaptic plasticity, widely described in the hippocampus and cortex. Though FXS is associated with hyperactivity, impaired social interaction, and the development of repetitive or stereotyped behaviors, all of which are influenced by striatal activity, few studies have investigated the function of FMRP here. Utilizing a cortical-striatal co-culture model, we find that striatal medium spiny neurons (MSNs) lacking FMRP fail to make normal increases in PSD95 expression over a short time period and have significant deficits in dendritic spine density and colocalized synaptic puncta at the later measured time point compared to wildtype (WT) MSNs. Acute expression of wtFMRP plasmid in Fmr1 KO co-cultures results in contrasting outcomes for these measures on MSNs at the more mature time point, reducing spine density across multiple spine types but making no significant changes in colocalized puncta. FMRP’s KH2 and RGG RNA-binding domains are required for normal elimination of PSD95, and interruption of these domains slightly favors elimination of immature spine types. Further, KH2 is required for normal levels of colocalized puncta. Our data are largely consistent with a basal role for FMRP and its RNA-binding domains in striatal synapse stabilization on developing MSNs, and in light of previous findings, suggest distinct regional and/or cell type-specific roles for FMRP in regulating synapse structure.

脆弱的X智力低下蛋白（FMRP）是一种RNA结合蛋白，介导数百种脑RNA的运输，稳定和翻译，它在调节突触功能中至关重要。FMRP的丧失（如脆性X综合征（FXS））是自闭症的主要单基因病因，并导致海马和皮层中结构和功能突触可塑性的改变。尽管FXS与过度活跃，社交互动受损以及重复性或刻板行为的发展相关，所有这些都受纹状体活动的影响，但很少有研究在此研究FMRP的功能。利用皮质-纹状体共培养模型，我们发现，缺乏FMRP的纹状体中棘神经元（MSN）在短时间内无法使PSD95表达正常增加，并且与野生型（WT）MSN相比，在较晚的测量时间点，树突棘密度和突触突点的共定位显着不足。wtFMRP质粒在小鼠中的急性表达调频1KO共培养的结果是，在更成熟的时间点，针对MSN采取的这些措施的结果截然相反，降低了多种脊柱类型的脊柱密度，但对共定位的泪点没有明显改变。FMRP的KH2和RGG RNA结合结构域是正常消除PSD95所必需的，这些结构域的中断稍微有利于消除未成熟的脊柱类型。此外，正常水平的共定位小点需要KH2。我们的数据在很大程度上与FMRP及其RNA结合结构域在发育中的MSN的纹状体突触稳定中的基础作用一致，并且根据以前的发现，表明FMRP在调节突触结构方面具有独特的区域和/或细胞类型特异性作用。