Peripheral Fragile X messenger ribonucleoprotein is required for the timely closure of a critical period for neuronal susceptibility in the ventral cochlear nucleus.
Peripheral Fragile X messenger ribonucleoprotein is required for the timely closure of a critical period for neuronal susceptibility in the ventral cochlear nucleus.
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DOI：
10.3389/fncel.2023.1186630
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发表时间：
2023
影响因子：
5.3
通讯作者：
Wang, Yuan
中科院分区：
文献类型：
--
作者：
Yu, Xiaoyan;Wang, Yuan
神经可塑性和关键时期的改变在神经发育疾病中很常见，包括脆性X综合征（FXS），这是导致自闭症的主要单基因原因。FXS以感觉功能障碍为特征，是脆性X信使核糖核蛋白1 （FMR1）基因沉默及其产物脆性X信使核糖核蛋白（FMRP）缺失的结果。FXS关键时期改变和感觉功能障碍的机制尚不清楚。在这里，我们在野生型和Fmr1敲除（KO）小鼠中进行了遗传和手术剥夺外周听觉输入，并研究了FMRP缺失对脱音诱导的腹侧耳蜗核（VCN）神经元变化和听觉脑干反应的影响。Fmr1 KO小鼠在关键时期的神经元细胞损失程度没有变化。但是，关键时期的结束被推迟了。重要的是，这种延迟在时间上与听觉灵敏度下降是一致的，这意味着与感觉输入有关。功能分析进一步确定了螺旋神经节到VCN信号传递的早发性和持久性改变，表明FMRP作用的外周部位。最后，我们生成了选择性缺失螺旋神经节而非VCN神经元FMRP的条件型Fmr1 KO （cKO）小鼠。cKO小鼠再现了Fmr1 KO小鼠VCN关键时期关闭的延迟，证实了耳蜗FMRP参与塑造大脑神经元关键时期的时间特征。总之，这些结果确定了神经发育发病的一种新的外周机制。
Alterations in neuronal plasticity and critical periods are common across neurodevelopmental diseases, including Fragile X syndrome (FXS), the leading single-gene cause of autism. Characterized with sensory dysfunction, FXS is the result of gene silencing of Fragile X messenger ribonucleoprotein 1 (FMR1) and loss of its product, Fragile X messenger ribonucleoprotein (FMRP). The mechanisms underlying altered critical period and sensory dysfunction in FXS are obscure. Here, we performed genetic and surgical deprivation of peripheral auditory inputs in wildtype and Fmr1 knockout (KO) mice across ages and investigated the effects of global FMRP loss on deafferentation-induced neuronal changes in the ventral cochlear nucleus (VCN) and auditory brainstem responses. The degree of neuronal cell loss during the critical period was unchanged in Fmr1 KO mice. However, the closure of the critical period was delayed. Importantly, this delay was temporally coincidental with reduced hearing sensitivity, implying an association with sensory inputs. Functional analyses further identified early-onset and long-lasting alterations in signal transmission from the spiral ganglion to the VCN, suggesting a peripheral site of FMRP action. Finally, we generated conditional Fmr1 KO (cKO) mice with selective deletion of FMRP in spiral ganglion but not VCN neurons. cKO mice recapitulated the delay in the VCN critical period closure in Fmr1 KO mice, confirming an involvement of cochlear FMRP in shaping the temporal features of neuronal critical periods in the brain. Together, these results identify a novel peripheral mechanism of neurodevelopmental pathogenesis.
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传入剥夺引起了小鼠耳蜗核中关键时期后与神经元存活相关的转录反应。
影响因子：
5.3
作者：
Harris, Julie A.;Iguchi, Fukuichiro;Seidl, Armin H.;Lurie, Diana I.;Rubel, Edwin W.
通讯作者：
Rubel, Edwin W.
DOI：
10.1002/cne.24959
发表时间：
2021-03
期刊：
The Journal of comparative neurology
影响因子：
--
作者：
Yu X;Wang X;Sakano H;Zorio DAR;Wang Y
通讯作者：
Wang Y
影响因子：
81.5
作者：
Hagerman, Randi J.;Berry-Kravis, Elizabeth;Hagerman, Paul J.
通讯作者：
Hagerman, Paul J.
影响因子：
5.3
作者：
Gabel, LA;Won, S;Fallon, JR
通讯作者：
Fallon, JR
影响因子：
5.3
作者：
Campagnola, Luke;Manis, Paul B.
通讯作者：
Manis, Paul B.