Visual-spatial learning impairments are associated with hippocampal PSD-95 protein dysregulation in a mouse model of fragile X syndrome
Visual-spatial learning impairments are associated with hippocampal PSD-95 protein dysregulation in a mouse model of fragile X syndrome
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DOI：
10.1097/wnr.0000000000000087
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发表时间：
2014-03-05
期刊：
影响因子：
1.7
通讯作者：
MacLeod, Lindsey S.
中科院分区：
文献类型：
--
作者：
Gandhi, Reno M.;Kogan, Cary S.;MacLeod, Lindsey S.
脆性 X 综合征是遗传性智力障碍的最常见原因，是由脆性 X 智力迟钝蛋白 (FMRP) 表达缺乏引起的。小鼠体外研究结果和人类死后尸检结果的特点是在缺乏 Fmrp/FMRP 的情况下树突棘异常。生化和电生理学研究已确定突触后密度蛋白 (PSD)-95 在树突形态中具有确定的作用，并且是 Fmrp 的分子靶点。 Fmrp 如何影响行为学习后 PSD-95 的表达尚不清楚。在当前的研究中，野生型对照小鼠和 Fmr1 敲除小鼠在 Hebb-Williams (H-W) 迷宫的子集中进行训练。测量了背海马 PSD-95 相对于稳定细胞骨架蛋白（β-微管蛋白）的蛋白水平。我们报告野生型小鼠中 PSD-95 蛋白水平显着上调，而 Fmr1 敲除小鼠中与训练相关的蛋白水平增加则减弱。此外，迷宫的平均总误差与 PSD-95 蛋白水平之间存在显着的负相关。确定系数表明 H-W 迷宫的平均总误差占 PSD-95 蛋白水平方差的 35%。这些新发现表明，PSD-95 相关的突触后可塑性降低可能会导致人类脆性 X 综合征患者的学习和记忆缺陷。
Fragile X syndrome is the most common cause of inherited intellectual disability and is caused by the lack of fragile X mental retardation protein (FMRP) expression. In-vitro findings in mice and post-mortem autopsies in humans are characterized by dendritic spine abnormalities in the absence of Fmrp/FMRP. Biochemical and electrophysiological studies have identified postsynaptic density protein (PSD)-95 as having an established role in dendritic morphology as well as a molecular target of Fmrp. How Fmrp affects the expression of PSD-95 following behavioral learning is unknown. In the current study, wild type controls and Fmr1 knockout mice were trained in a subset of the Hebb-Williams (H-W) mazes. Dorsal hippocampal PSD-95 protein levels relative to a stable cytoskeleton protein (beta-tubulin) were measured. We report a significant upregulation of PSD-95 protein levels in wild type mice, whereas training-related protein increases were blunted in Fmr1 knockout mice. In addition, there was a significant negative correlation between mean total errors on the mazes and PSD-95 protein levels. The coefficient of determination indicated that the mean total errors on the H-W mazes accounted for 35% of the variance in PSD-95 protein levels. These novel findings suggest that reduced PSD-95-associated postsynaptic plasticity may contribute to the learning and memory deficits observed in human fragile X syndrome patients.