title: Seizure-dependent mTOR activation in 5-HT neurons promotes autism-like behaviors in mice.
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.
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: McMahon
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Wilson
authors.initials: W
authors.lastname: Yu
authors.affiliation: Center for Cardiovascular Sciences, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Haihua
authors.initials: H
authors.lastname: Feng
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Meghan
authors.initials: M
authors.lastname: Helm
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McMahon
authors.affiliation: Center for Cardiovascular Sciences, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Xinjun
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Damian
authors.initials: D
authors.lastname: Shin
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA. Electronic address: huangy@mail.amc.edu.
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000188:drug therapy* / Q000378:metabolism*; D001522:Behavior, Animal / Q000502:physiology*; D004195:Disease Models, Animal; D004827:Epilepsy / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011903:Raphe Nuclei / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D012701:Serotonin; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: 5-HT; Autism; Epilepsy; TSC; mTOR