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Serotonin (5-HT) neuron-specific inactivation of Cadherin-13 impacts 5-HT system formation and cognitive function.
Neuropharmacology ( IF 4.7 ) Pub Date : 2020-02-27 , DOI: 10.1016/j.neuropharm.2020.108018
Andrea Forero 1 , Hsing-Ping Ku 1 , Ana Belén Malpartida 1 , Sina Wäldchen 2 , Judit Alhama-Riba 1 , Christina Kulka 1 , Benjamin Aboagye 1 , William H J Norton 3 , Andrew M J Young 3 , Yu-Qiang Ding 4 , Robert Blum 5 , Markus Sauer 2 , Olga Rivero 1 , Klaus-Peter Lesch 6
Affiliation  

Genome-wide screening approaches identified the cell adhesion molecule Cadherin-13 (CDH13) as a risk factor for neurodevelopmental disorders, nevertheless the contribution of CDH13 to the disease mechanism remains obscure. CDH13 is involved in neurite outgrowth and axon guidance during early brain development and we previously provided evidence that constitutive CDH13 deficiency influences the formation of the raphe serotonin (5-HT) system by modifying neuron-radial glia interaction. Here, we dissect the specific impact of CDH13 on 5-HT neuron development and function using a 5-HT neuron-specific Cdh13 knockout mouse model (conditional Cdh13 knockout, Cdh13 cKO). Our results show that exclusive inactivation of CDH13 in 5-HT neurons selectively increases 5-HT neuron density in the embryonic dorsal raphe, with persistence into adulthood, and serotonergic innervation of the developing prefrontal cortex. At the behavioral level, adult Cdh13 cKO mice display delayed acquisition of several learning tasks and a subtle impulsive-like phenotype, with decreased latency in a sociability paradigm alongside with deficits in visuospatial memory. Anxiety-related traits were not observed in Cdh13 cKO mice. Our findings further support the critical role of CDH13 in the development of dorsal raphe 5-HT circuitries, a mechanism that may underlie specific clinical features observed in neurodevelopmental disorders.

中文翻译:

Cadherin-13的5-羟色胺(5-HT)神经元特异性失活会影响5-HT系统的形成和认知功能。

全基因组筛选方法确定细胞粘附分子Cadherin-13(CDH13)是神经发育障碍的危险因素,但是CDH13对疾病机制的贡献仍然不清楚。CDH13在早期大脑发育过程中参与神经突的生长和轴突的引导,并且我们先前提供的证据表明,本构性CDH13缺乏会通过修饰神经元-g神经胶质细胞相互作用而影响缝状5-羟色胺(5-HT)系统的形成。在这里,我们使用5-HT神经元特异性Cdh13基因敲除小鼠模型(条件Cdh13基因敲除,Cdh13 cKO)剖析CDH13对5-HT神经元发育和功能的特定影响。我们的结果表明,5-HT神经元中CDH13的完全失活选择性地增加了胚胎背沟中5-HT神经元的密度,并持续到成年,和额叶皮质神经的神经支配。在行为水平上,成年Cdh13 cKO小鼠表现出延迟获取一些学习任务和微妙的冲动样表型,在社交范式中的潜伏期缩短,同时视觉空间记忆也不足。在Cdh13 cKO小鼠中未观察到焦虑相关性状。我们的发现进一步支持CDH13在背缝5-HT回路发育中的关键作用,该机制可能是在神经发育障碍中观察到的特定临床特征的基础。在Cdh13 cKO小鼠中未观察到焦虑相关性状。我们的发现进一步支持CDH13在背缝5-HT回路发育中的关键作用,该机制可能是在神经发育障碍中观察到的特定临床特征的基础。在Cdh13 cKO小鼠中未观察到焦虑相关性状。我们的发现进一步支持CDH13在背缝5-HT回路发育中的关键作用,该机制可能是在神经发育障碍中观察到的特定临床特征的基础。
更新日期:2020-02-28
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