Postnatal Arx transcriptional activity regulates functional properties of PV interneurons.
Postnatal Arx transcriptional activity regulates functional properties of PV interneurons.
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DOI：
10.1016/j.isci.2020.101999
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发表时间：
2021-01-22
期刊：
影响因子：
5.8
通讯作者：
Marsh ED
中科院分区：
文献类型：
--
作者：
Joseph DJ;Von Deimling M;Hasegawa Y;Cristancho AG;Ahrens-Nicklas RC;Rogers SL;Risbud R;McCoy AJ;Marsh ED
转录因子Aristaless-related X-linked gene（Arx）是早发性癫痫性脑病（EOEEs）的单基因因子，也是脑发育早期阶段的基本调节因子。然而，Arx的表达仍然存在于成熟的GABA能神经元中，其作用尚不清楚。为了解决这个问题，我们产生了一个条件性基因敲除（CKO）小鼠，其中出生后的Arx被消融在小清蛋白中间神经元（PVIs）。CKO小鼠的脑电图（EEG）记录显示θ振荡增加和偶尔癫痫发作的发生。行为分析发现焦虑增加。荧光激活细胞分选（FACS）PVIs的全基因组测序显示，Arx通过主要与突触和细胞外基质途径相关的基因影响网络兴奋性。全细胞记录揭示了各种内在和突触特性的显著低兴奋性。这些结果揭示了出生后Arx在PVIs中的表达在神经回路控制中的重要作用，并且仅这些作用的功能障碍就可能导致EOEE样网络异常。Arx CKO小鼠表现出异常的θ节律、偶尔的癫痫发作和焦虑PV中间神经元中Arx的缺失广泛地改变了它们的基因表达谱PV中间神经元周围的神经元周网在Arx CKO小鼠中被改变PV中间神经元中Arx的缺失改变了它们的内在和突触特性行为神经科学;分子神经科学;细胞神经科学;转录组学
The transcription factor Aristaless-related X-linked gene (Arx) is a monogenic factor in early onset epileptic encephalopathies (EOEEs) and a fundamental regulator of early stages of brain development. However, Arx expression persists in mature GABAergic neurons with an unknown role. To address this issue, we generated a conditional knockout (CKO) mouse in which postnatal Arx was ablated in parvalbumin interneurons (PVIs). Electroencephalogram (EEG) recordings in CKO mice revealed an increase in theta oscillations and the occurrence of occasional seizures. Behavioral analysis uncovered an increase in anxiety. Genome-wide sequencing of fluorescence activated cell sorted (FACS) PVIs revealed that Arx impinged on network excitability via genes primarily associated with synaptic and extracellular matrix pathways. Whole-cell recordings revealed prominent hypoexcitability of various intrinsic and synaptic properties. These results revealed important roles for postnatal Arx expression in PVIs in the control of neural circuits and that dysfunction in those roles alone can cause EOEE-like network abnormalities. Arx CKO mice displayed abnormal theta rhythms, occasional seizures, and anxiety Loss of Arx in PV interneurons broadly altered their gene expression profiles The perineuronal net around PV interneurons was altered in Arx CKO mice Loss of Arx in PV interneurons altered their intrinsic and synaptic properties Behavioral Neuroscience ; Molecular Neuroscience; Cellular Neuroscience; Transcriptomics
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