Seizure-dependent mTOR activation in 5-HT neurons promotes autism-like behaviors in mice

NEUROBIOLOGY OF DISEASE

卷:73

Article

McMahon, John J.¹  Yu, Wilson¹  Yang, Jun²  Feng, Haihua¹  Helm, Meghan¹  McMahon, Elizabeth¹  Zhu, Xinjun²  Shin, Damian¹  Huang, Yunfei¹ 

[1] Albany Med Coll, Ctr Neuropharmacol & Neurosci, Albany, NY 12208 USA

[2] Albany Med Coll, Ctr Cardiovasc Sci, Albany, NY 12208 USA

关键词: mTOR;    Autism;    Epilepsy;    5-HT;    TSC;   

DOI  :  10.1016/j.nbd.2014.10.004

来源: Elsevier

【 摘 要 】

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 Tsc1(flox/flox);Slc6a4-cre mice, in which mTOR is restrictively hyperactivated in 5-HT neurons. Tsc1(flox/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. (C) 2015 Elsevier Inc. All rights reserved.

【 授权许可】

Free