Ube3a loss increases excitability and blunts orientation tuning in the visual cortex of Angelman syndrome model mice.
Ube3a loss increases excitability and blunts orientation tuning in the visual cortex of Angelman syndrome model mice.
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Ube3a 缺失会增加天使综合征模型小鼠视觉皮层的兴奋性并减弱方向调节。
DOI：
10.1152/jn.00618.2016
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发表时间：
2017
影响因子：
2.5
通讯作者：
Philpot,BenjaminD
中科院分区：
文献类型：
--
作者：
Wallace,MichaelL;vanWoerden,GeeskeM;Elgersma,Ype;Smith,SpencerL;Philpot,BenjaminD
Angelman 综合征 (AS) 是一种由母体遗传的 UBE3A 等位基因缺失引起的神经发育障碍。Ube3aSTOP/p+小鼠重现了人类 AS 的主要特征，并允许有条件地恢复母体 Ube3a 并表达 Cre 重组酶。我们最近发现 AS 模型小鼠表现出对视觉皮层 (L)2/3 层锥体神经元的抑制驱动减少，这导致突触兴奋/抑制失衡。然而，目前尚不清楚这种抑制驱动力的丧失如何影响体内的神经回路。在这里，我们检查了单个神经元的视觉皮层反应特性，以探索 Ube3 缺失对完整皮层回路和处理的影响。使用体内膜片钳电生理学，我们测量了对照小鼠、Ube3a缺陷小鼠和在GABA能神经元中条件性恢复Ube3的小鼠的L2/3规则尖峰（RS）神经元中对方波漂移光栅的视觉诱发反应。我们发现 Ube3a 缺陷小鼠在体内表现出增强的锥体神经元兴奋性以及较弱的方向调节能力。这些观察结果首次显示了 AS 模型中皮质计算的变化，并提出了 AS 皮质功能障碍的基础。新的和值得注意的Angelman 综合征 (AS) 是一种由 UBE3A 基因缺失引起的严重神经发育障碍。利用体内电生理记录，我们描述了 AS 小鼠模型中的视觉皮层功能障碍。通过恢复抑制性神经元中的 Ube3a 可以改善 AS 模型小鼠的异常细胞特性。这些发现表明抑制性神经元在 AS 的发病机制中发挥着重要作用。
Angelman syndrome (AS) is a neurodevelopmental disorder caused by loss of the maternally inherited allele ofUBE3A.Ube3aSTOP/p+mice recapitulate major features of AS in humans and allow conditional reinstatement of maternalUbe3awith the expression of Cre recombinase. We have recently shown that AS model mice exhibit reduced inhibitory drive onto layer (L)2/3 pyramidal neurons of visual cortex, which contributes to a synaptic excitatory/inhibitory imbalance. However, it remains unclear how this loss of inhibitory drive affects neural circuits in vivo. Here we examined visual cortical response properties in individual neurons to explore the consequences ofUbe3aloss on intact cortical circuits and processing. Using in vivo patch-clamp electrophysiology, we measured the visually evoked responses to square-wave drifting gratings in L2/3 regular-spiking (RS) neurons in control mice,Ube3a-deficient mice, and mice in whichUbe3awas conditionally reinstated in GABAergic neurons. We found thatUbe3a-deficient mice exhibited enhanced pyramidal neuron excitability in vivo as well as weaker orientation tuning. These observations are the first to show alterations in cortical computation in an AS model, and they suggest a basis for cortical dysfunction in AS.NEW & NOTEWORTHYAngelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of the geneUBE3A. Using electrophysiological recording in vivo, we describe visual cortical dysfunctions in a mouse model of AS. Aberrant cellular properties in AS model mice could be improved by reinstatingUbe3ain inhibitory neurons. These findings suggest that inhibitory neurons play a substantial role in the pathogenesis of AS.