title: mTOR Inhibition ameliorates cognitive and affective deficits caused by Disc1 knockdown in adult-born dentate granule neurons.
abstract: Abnormalities during brain development are thought to cause psychiatric illness and other neurodevelopmental disorders. However, developmental processes such as neurogenesis continue in restricted brain regions of adults, and disruptions of these processes could contribute to the phenotypes of neurodevelopmental disorders. As previously reported, we show that Disc1 knockdown specifically in adult-born dentate gyrus (DG) neurons results in increased mTOR signaling, hyperexcitability, and neuronal structure deficits. Disc1 knockdown also resulted in pronounced cognitive and affective deficits, which could be reversed when the affected DG neurons were inactivated. Importantly, reversing increases in mTOR signaling with an FDA-approved inhibitor both prevented and treated these behavioral deficits, even when associated structural deficits were not reversed. Our findings suggest that a component of the affective and cognitive phenotypes in neurodevelopmental disorders may be caused by disruptions in adult-born neurons. Consequently, treatments directed at this cell population may have a significant impact on these phenotypes.
authors: Departments of Neurobiology, Psychology, and Psychiatry, Integrative Center for Learning and Memory and Brain Research Institute, UCLA, Los Angeles, CA 90095, USA.
authors: Miou
authors: M
authors: Zhou
authors: Weidong
authors: W
authors: Li
authors: Shan
authors: S
authors: Huang
authors: Juan
authors: J
authors: Song
authors: Ju Young
authors: JY
authors: Kim
authors: Xiaoli
authors: X
authors: Tian
authors: Eunchai
authors: E
authors: Kang
authors: Yoshitake
authors: Y
authors: Sano
authors: Cindy
authors: C
authors: Liu
authors: J
authors: J
authors: Balaji
authors: Shumin
authors: S
authors: Wu
authors: Yu
authors: Y
authors: Zhou
authors: Ying
authors: Y
authors: Zhou
authors: Sherveen N
authors: SN
authors: Parivash
authors: Dan
authors: D
authors: Ehninger
authors: Lin
authors: L
authors: He
authors: Hongjun
authors: H
authors: Song
authors: Guo-Li
authors: GL
authors: Ming
authors: Alcino J
authors: AJ
authors: Silva
mesh_terms: D000375:Aging; D000818:Animals; D003071:Cognition / Q000502:physiology*; D018891:Dentate Gyrus / Q000166:cytology*; D055785:Gene Knockdown Techniques; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics; D009474:Neurons / Q000166:cytology*; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: C498794:Disc1 protein, mouse; D009419:Nerve Tissue Proteins; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases