Deletion of Fmr1 in parvalbumin-expressing neurons results in dysregulated translation and selective behavioral deficits associated with fragile X syndrome.
Deletion of Fmr1 in parvalbumin-expressing neurons results in dysregulated translation and selective behavioral deficits associated with fragile X syndrome.
复制标题
DOI：
10.1186/s13229-022-00509-2
复制
发表时间：
2022-06-29
期刊：
影响因子：
6.2
通讯作者：
中科院分区：
文献类型：
--
作者：
脆性X综合征（FXS）是自闭症谱系障碍和智力残疾最常见的遗传原因，是由脆性X智力迟钝蛋白（FMRP）表达缺乏引起的。FMRP是一种mRNA结合蛋白，具有mRNA转运、定位和翻译控制功能。在Fmr1敲除小鼠中，翻译失调与病理生理有关，包括突触功能和树突形态异常，以及自闭症样行为表型。在缺乏Fmr1的小鼠中，FMRP在兴奋性神经元形态和功能中的作用已经得到了很好的研究，但Fmr1缺失对抑制性神经元的影响仍然较少。此外，不同细胞类型的FMRP对FXS病理生理的贡献尚未明确。我们试图描述小白蛋白或生长抑素表达神经元中FMRP缺失是否会导致小鼠fxs样缺陷。我们使用Cre-lox重组酶技术，在表达小白蛋白或生长抑素的细胞中产生了两种缺乏FMRP的条件敲除小鼠，并进行了一系列行为测试，以评估运动功能、焦虑、重复、刻板印象、社会行为以及学习和记忆。此外，我们使用荧光非规范氨基酸标记和免疫染色来确定在表达小白蛋白或生长抑素的神经元中，新生蛋白合成是否失调。Fmr1敲除小鼠海马小白蛋白和生长抑素表达抑制神经元中新生蛋白合成升高。表达小蛋白的神经元中Fmr1的细胞类型特异性缺失导致焦虑样行为、社交行为受损和新生蛋白合成失调。相比之下，在表达生长抑素的神经元中删除Fmr1不会导致行为异常，也不会显著影响新生蛋白合成。这是关于两种特定亚型抑制性神经元中FMRP缺失如何与不同的fxs样异常相关的第一篇报道。我们所建立的小鼠模型受到小白蛋白或生长抑素表达细胞中FMRP的全身敲除的限制，需要进一步的研究来建立细胞缺陷与fxs样行为之间的因果关系。我们的研究结果表明，FMRP在表达小蛋白的神经元中具有细胞类型特异性作用，可调节与FXS相关的不同行为特征。在线版本包含补充材料，可在10.1186/s13229-022-00509-2获得。
Fragile X syndrome (FXS), the most common genetic cause of autism spectrum disorder and intellectual disability, is caused by the lack of fragile X mental retardation protein (FMRP) expression. FMRP is an mRNA binding protein with functions in mRNA transport, localization, and translational control. In Fmr1 knockout mice, dysregulated translation has been linked to pathophysiology, including abnormal synaptic function and dendritic morphology, and autistic-like behavioral phenotypes. The role of FMRP in morphology and function of excitatory neurons has been well studied in mice lacking Fmr1, but the impact of Fmr1 deletion on inhibitory neurons remains less characterized. Moreover, the contribution of FMRP in different cell types to FXS pathophysiology is not well defined. We sought to characterize whether FMRP loss in parvalbumin or somatostatin-expressing neurons results in FXS-like deficits in mice. We used Cre-lox recombinase technology to generate two lines of conditional knockout mice lacking FMRP in either parvalbumin or somatostatin-expressing cells and carried out a battery of behavioral tests to assess motor function, anxiety, repetitive, stereotypic, social behaviors, and learning and memory. In addition, we used fluorescent non-canonical amino acid tagging along with immunostaining to determine whether de novo protein synthesis is dysregulated in parvalbumin or somatostatin-expressing neurons. De novo protein synthesis was elevated in hippocampal parvalbumin and somatostatin-expressing inhibitory neurons in Fmr1 knockout mice. Cell type-specific deletion of Fmr1 in parvalbumin-expressing neurons resulted in anxiety-like behavior, impaired social behavior, and dysregulated de novo protein synthesis. In contrast, deletion of Fmr1 in somatostatin-expressing neurons did not result in behavioral abnormalities and did not significantly impact de novo protein synthesis. This is the first report of how loss of FMRP in two specific subtypes of inhibitory neurons is associated with distinct FXS-like abnormalities. The mouse models we generated are limited by whole body knockout of FMRP in parvalbumin or somatostatin-expressing cells and further studies are needed to establish a causal relationship between cellular deficits and FXS-like behaviors. Our findings indicate a cell type-specific role for FMRP in parvalbumin-expressing neurons in regulating distinct behavioral features associated with FXS. The online version contains supplementary material available at 10.1186/s13229-022-00509-2.
登录
查看更多内容
影响因子：
5.3
作者：
Filice F;Janickova L;Henzi T;Bilella A;Schwaller B
通讯作者：
Schwaller B
影响因子：
12.8
作者：
Babaev O;Piletti Chatain C;Krueger-Burg D
通讯作者：
Krueger-Burg D
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
30.8
作者：
DEVYS, D;LUTZ, Y;MANDEL, JL
通讯作者：
MANDEL, JL
影响因子：
3.7
作者：
Ariza, Jeanelle;Rogers, Haille;Martinez-Cerdeno, Veronica
通讯作者：
Martinez-Cerdeno, Veronica