title: Overexpression of Telomerase Reverse Transcriptase Induces Autism-like Excitatory Phenotypes in Mice.
abstract: In addition to its classical role as a regulator of telomere length, recent reports suggest that telomerase reverse transcriptase (TERT) plays a role in the transcriptional regulation of gene expression such as β-catenin-responsive pathways. Silencing or over-expression of TERT in cultured NPCs demonstrated that TERT induced glutamatergic neuronal differentiation. During embryonic brain development, expression of transcription factors involved in glutamatergic neuronal differentiation was increased in mice over-expressing TERT (TERT-tg mice). We observed increased expression of NMDA receptor subunits and phosphorylation of α-CaMKII in TERT-tg mice. TERT-tg mice showed autism spectrum disorder (ASD)-like behavioral phenotypes as well as lowered threshold against electrically induced seizure. Interestingly, the NMDA receptor antagonist memantine restored behavioral abnormalities in TERT-tg mice. Consistent with the alteration in excitatory/inhibitory (E/I) ratio, TERT-tg mice showed autism-like behaviors, abnormal synaptic organization, and function in mPFC suggesting the role of altered TERT activity in the manifestation of ASD, which is further supported by the significant association of certain SNPs in Korean ASD patients.
authors.affiliation: Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Konkuk University, Seoul, South Korea.
authors.forename: Ki Chan
authors.initials: KC
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, Konkuk University, Seoul, South Korea.
authors.forename: Jeehae
authors.initials: J
authors.lastname: Rhee
authors.affiliation: Department of Neuropsychiatry, Seoul National University Bungdang Hospital, Seongnam, South Korea.
authors.forename: Jong-Eun
authors.initials: JE
authors.lastname: Park
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, South Korea.
authors.forename: Dong-Keun
authors.initials: DK
authors.lastname: Lee
authors.affiliation: Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Konkuk University, Seoul, South Korea.|School of Medicine, Konkuk University, Seoul, South Korea.|KU Open Innovation Center, Konkuk University, Seoul, South Korea.
authors.forename: Chang Soon
authors.initials: CS
authors.lastname: Choi
authors.affiliation: Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Konkuk University, Seoul, South Korea.|School of Medicine, Konkuk University, Seoul, South Korea.|KU Open Innovation Center, Konkuk University, Seoul, South Korea.
authors.forename: Ji-Woon
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, College of Science, Yonsei University, Seoul, South Korea.
authors.forename: Han-Woong
authors.initials: HW
authors.lastname: Lee
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, South Korea.
authors.forename: Mi-Ryoung
authors.initials: MR
authors.lastname: Song
authors.affiliation: Department of Neuropsychiatry, Seoul National University Bungdang Hospital, Seongnam, South Korea.
authors.forename: Hee Jeong
authors.initials: HJ
authors.lastname: Yoo
authors.affiliation: Department of Biological Sciences, Konkuk University, Seoul, South Korea.
authors.forename: ChiHye
authors.initials: C
authors.lastname: Chung
authors.affiliation: Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Konkuk University, Seoul, South Korea. chanyshin@kku.ac.kr.|School of Medicine, Konkuk University, Seoul, South Korea. chanyshin@kku.ac.kr.|KU Open Innovation Center, Konkuk University, Seoul, South Korea. chanyshin@kku.ac.kr.|Department of Pharmacology, School of Medicine and Center for Geriatric Neuroscience Research, IBST, Konkuk University, 1 Hwayang-Dong Kwangjin-Gu, Seoul, 143-701, South Korea. chanyshin@kku.ac.kr.
authors.forename: Chan Young
authors.initials: CY
authors.lastname: Shin
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D001522:Behavior, Animal; D001921:Brain / Q000196:embryology; D002454:Cell Differentiation; D002478:Cells, Cultured; D047108:Embryonic Development; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D005971:Glutamates / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D008559:Memantine / Q000494:pharmacology / Q000627:therapeutic use; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D010641:Phenotype; D034741:RNA, Small Interfering / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure; D019098:Telomerase / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D005971:Glutamates; D034741:RNA, Small Interfering; D016194:Receptors, N-Methyl-D-Aspartate; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D019098:Telomerase; D008559:Memantine
keywords: Autism spectrum disorder; Excitatory/Inhibitory imbalance; Glutamatergic neuron; Memantine; NMDA receptor; Telomerase reverse transcriptase