Audiogenic Seizures in the Fmr1 Knock-Out Mouse Are Induced by Fmr1 Deletion in Subcortical, VGlut2-Expressing Excitatory Neurons and Require Deletion in the Inferior Colliculus
Audiogenic Seizures in the Fmr1 Knock-Out Mouse Are Induced by Fmr1 Deletion in Subcortical, VGlut2-Expressing Excitatory Neurons and Require Deletion in the Inferior Colliculus
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DOI：
10.1523/jneurosci.0886-19.2019
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发表时间：
2019-12-04
影响因子：
5.3
通讯作者：
Gibson, Jay R.
中科院分区：
文献类型：
--
作者：
Gonzalez, Darya;Tomasek, Madison;Gibson, Jay R.
脆性X综合征（FXS）是遗传性智力残疾的最常见形式，也是自闭症的主要单基因原因。FXS和自闭症的一个症状是感觉超敏反应（也称为感觉过度反应）。可能与此相关，听源性癫痫发作（AGS）可以说是FXS小鼠模型-Fmr 1敲除（KO）小鼠中最稳健的行为表型。因此，AGS可以被认为是感觉超敏反应的小鼠模型。过度活跃的回路被假设为FXS和Fmr 1 KO小鼠患者许多脑区功能障碍的基础，AGS可能是这一结果。但是，在Fmr 1 KO中，特定的细胞类型和潜在的AGS大脑区域是未知的。我们在不同的细胞群中使用了Fmr 1的条件性缺失或表达，以确定这些细胞中的Fmr 1缺失对于男性的AGS表型是足够的还是必要的。我们的数据表明，Fmr 1的缺失，表达囊泡谷氨酸转运体2（VGlut 2），并位于皮层下的大脑区域的谷氨酸能神经元是足够的和必要的，导致AGSs。此外，在AGSs中，下丘神经元中Fmr 1的缺失是必需的。当我们证明的必要性，我们表明，Fmr 1的表达，无论是在较大的人口VGIut 2的表达mammatergic神经元或较小的人口下丘mammatergic神经元，否则在一个Fmr 1基因敲除小鼠-消除AGSs。因此，在FXS和自闭症中靶向这些神经元群体可能是减轻感觉超敏反应的治疗策略的一部分。
Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and the leading monogenetic cause of autism. One symptom of FXS and autism is sensory hypersensitivity (also called sensory over-responsivity). Perhaps related to this, the audiogenic seizure (AGS) is arguably the most robust behavioral phenotype in the FXS mouse model-the Fmr1 knock-out (KO) mouse. Therefore, the AGS may be considered a mouse model of sensory hypersensitivity. Hyperactive circuits are hypothesized to underlie dysfunction in a number of brain regions in patients with FXS and Fmr1 KO mice, and the AGS may be a result of this. But the specific cell types and brain regions underlying AGSs in the Fmr1 KO are unknown. We used conditional deletion or expression of Fmr1 in different cell populations to determine whether Fmr1 deletion in those cells was sufficient or necessary, respectively, for the AGS phenotype in males. Our data indicate that Fmr1 deletion in glutamatergic neurons that express vesicular glutamate transporter 2 (VGlut2) and are located in subcortical brain regions is sufficient and necessary to cause AGSs. Furthermore, the deletion of Fmr1 in glutamatergic neurons of the inferior colliculus is necessary for AGSs. When we demonstrate necessity, we show that Fmr1 expression in either the larger population of VGIut2-expressing glutamatergic neurons or the smaller population of inferior collicular glutamatergic neurons-in an otherwise Fmr1 KO mouse- eliminates AGSs. Therefore, targeting these neuronal populations in FXS and autism may be part of a therapeutic strategy to alleviate sensory hypersensitivity.