Seizure-dependent mTOR activation in 5-HT neurons promotes autism-like behaviors in mice.
Seizure-dependent mTOR activation in 5-HT neurons promotes autism-like behaviors in mice.
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5-HT神经元中的癫痫发作依赖性mTOR激活促进了小鼠的自闭症行为。
DOI：
10.1016/j.nbd.2014.10.004
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发表时间：
2015-01
影响因子：
6.1
通讯作者：
Huang, Yunfei
中科院分区：
文献类型：
--
作者：
McMahon, John J.;Yu, Wilson;Yang, Jun;Feng, Haihua;Helm, Meghan;McMahon, Elizabeth;Zhu, Xinjun;Shin, Damian;Huang, Yunfei
癫痫和自闭症谱系障碍(ASD)是彼此常见的共病。尽管这两种疾病之间普遍存在相关性，但很少有研究能够阐明机制上的联系。我们证明，小鼠前脑特异性TSC1缺失会导致癫痫和自闭症样行为，并伴随着5-羟色胺神经传递的中断。我们发现癫痫样活动传播到中缝核团，导致癫痫依赖的5-羟色胺神经元mTOR的过度激活。为了分析5-羟色胺神经元中mTOR高活性是否足以概括为孤独症样表型，我们使用了Tsc1flx/Flox；SLC6A4-cre小鼠，在这些小鼠中，5-羟色胺神经元中mTOR限制性地高激活。SLC6A4-cre小鼠表现出5-羟色胺系统的改变和自闭症样行为，但没有引起癫痫。雷帕霉素在这些小鼠中的治疗足以挽救这种表型。我们的结论是，癫痫发作活动扩散到脑干能够促进中缝核团mTOR的过度激活，这反过来又促进了自闭症样行为。因此，我们的研究提供了一种新的机制，描述了癫痫如何促进孤独症样行为的发展，并提出了治疗孤独症的新策略。
Epilepsy and autism spectrum disorder (ASD) are common comorbidities of one another. Despite the prevalent correlation between the two disorders, few studies have been able to elucidate a mechanistic link. We demonstrate that forebrain specific Tsc1 deletion in mice causes epilepsy and autism-like behaviors, concomitant with disruption of 5-HT neurotransmission. We find that epileptiform activity propagates to the raphe nuclei, resulting in seizure-dependent hyperactivation of mTOR in 5-HT neurons. To dissect whether mTOR hyperactivity in 5-HT neurons alone was sufficient to recapitulate an autism-like phenotype we utilized Tsc1flox/flox;Slc6a4-cre mice, in which mTOR is restrictively hyperactivated in 5-HT neurons. Tsc1flox/flox;Slc6a4-cre mice displayed alterations of the 5-HT system and autism-like behaviors, without causing epilepsy. Rapamycin treatment in these mice was sufficient to rescue the phenotype. We conclude that the spread of seizure activity to the brainstem is capable of promoting hyperactivation of mTOR in the raphe nuclei, which in turn promotes autism-like behaviors. Thus our study provides a novel mechanism describing how epilepsy can contribute to the development of autism-like behaviors, suggesting new therapeutic strategies for autism.
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影响因子：
4.2
作者：
Grider MH;Park D;Spencer DM;Shine HD
通讯作者：
Shine HD
DOI：
10.1523/jneurosci.4891-12.2013
发表时间：
2013-03-06
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Dzirasa K;Kumar S;Sachs BD;Caron MG;Nicolelis MA
通讯作者：
Nicolelis MA
影响因子：
3.7
作者：
Kane MJ;Angoa-Peréz M;Briggs DI;Sykes CE;Francescutti DM;Rosenberg DR;Kuhn DM
通讯作者：
Kuhn DM
影响因子：
2.5
作者：
Lin, Wan-hui;Huang, Hua-pin;Lin, Ji-lan
通讯作者：
Lin, Ji-lan
影响因子：
17.7
作者：
Hollander, Eric;Soorya, Latha;Settipani, Cara
通讯作者：
Settipani, Cara