A mouse model of Timothy syndrome exhibits altered social competitive dominance and inhibitory neuron development.,FEBS Open Bio

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A mouse model of Timothy syndrome exhibits altered social competitive dominance and inhibitory neuron development.
FEBS Open Bio ( IF 2.8 ) Pub Date : 2020-07-19 , DOI: 10.1002/2211-5463.12924
Shin-Ichiro Horigane _{1,

2} , Yukihiro Ozawa _{1,

2,

3} , Jun Zhang _{1,

2} , Hiroe Todoroki ₄ , Pan Miao _{1,

2} , Asahi Haijima _{4,

5} , Yuchio Yanagawa ₆ , Shuhei Ueda _{1,

2} , Shigeo Nakamura ₃ , Masaki Kakeyama _{4,

5} , Sayaka Takemoto-Kimura _{1,

2,

7}

Affiliation

Multiple genetic factors related to autism spectrum disorder (ASD) have been identified, but the biological mechanisms remain obscure. Timothy syndrome (TS), associated with syndromic ASD, is caused by a gain‐of‐function mutation, G406R, in the pore‐forming subunit of L‐type Ca²⁺ channels, Ca_v1.2. In this study, a mouse model of TS, TS2‐neo, was used to enhance behavioral phenotyping and to identify developmental anomalies in inhibitory neurons. Using the IntelliCage, which enables sequential behavioral tasks without human handling and mouse isolation stress, high social competitive dominance was observed in TS2‐neo mice. Furthermore, histological analysis demonstrated inhibitory neuronal abnormalities in the neocortex, including an excess of smaller‐sized inhibitory presynaptic terminals in the somatosensory cortex of young adolescent mice and higher numbers of migrating inhibitory neurons from the medial ganglionic eminence during embryonic development. In contrast, no obvious changes in excitatory synaptic terminals were found. These novel neural abnormalities in inhibitory neurons of TS2‐neo mice may result in a disturbed excitatory/inhibitory (E/I) balance, a key feature underlying ASD.

中文翻译：

蒂莫西综合征小鼠模型表现出社会竞争优势和抑制性神经元发育的改变。

与自闭症谱系障碍（ASD）相关的多种遗传因素已被确定，但其生物学机制仍不清楚。蒂莫西综合征 (TS) 与综合征型 ASD 相关，是由 L 型 Ca ²⁺通道的成孔亚基 Ca _v 1.2 中的功能获得性突变 G406R 引起的。在这项研究中，使用 TS 小鼠模型 TS2-neo 来增强行为表型并识别抑制性神经元的发育异常。使用 IntelliCage，无需人工处理和小鼠隔离压力即可实现连续的行为任务，在 TS2-neo 小鼠中观察到高度的社会竞争优势。此外，组织学分析表明新皮质中存在抑制性神经元异常，包括年轻小鼠体感皮层中过多的较小尺寸的抑制性突触前末梢以及胚胎发育过程中从内侧神经节隆起迁移的大量抑制性神经元。相反，兴奋性突触末梢没有发现明显变化。 TS2-neo 小鼠抑制性神经元中的这些新的神经异常可能会导致兴奋/抑制 (E/I) 平衡紊乱，这是自闭症谱系障碍 (ASD) 的一个关键特征。

更新日期：2020-07-19

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