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

John J. McMahon, Wilson Yu, Jun Yang, Haihua Feng, Meghan Helm, Elizabeth McMahon, Xinjun Zhu, Damian Shin, Yunfei Huang

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)296-306
Number of pages11
JournalNeurobiology of Disease
Volume73
DOIs
StatePublished - Jan 1 2015

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health by the grant R01NS062068-04 (to Y.H.)

Keywords

  • 5-HT
  • Autism
  • Epilepsy
  • MTOR
  • TSC

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