Biomolecules & Therapeutics  
Sex Differences in Autism-Like Behavioral Phenotypes and Postsynaptic Receptors Expression in the Prefrontal Cortex of TERT Transgenic Mice
Ki Chan Kim1,†,ψ, Kyu Suk Cho1,†, Sung Min Yang1,†, Edson Luck Gonzales1, Schley Valencia1, Pyeong Hwa Eun1, Chang Soon Choi1, Darine Froy Mabunga1, Ji-Woon Kim1, Judy Kyoungju Noh2, Hee Jin Kim3, Se Jin Jeon4, Seol-Heui Han1, Geon Ho Bahn5,* and Chan Young Shin1,*
1Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Konkuk University, Seoul 05029, Republic of Korea, 2College of Human Ecology, Cornell University, Ithaca, New York 14853, United States of America, 3Uimyung Research Institute for Neuroscience, School of Pharmacy, Sahmyook University, Seoul 01795, 4Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, 5Department of Neuropsychiatry, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
E-mail: chanyshin@kku.ac.kr (Shin CY), mompeian@khu.ac.kr (GH Bahn)
Tel: +82-2-2030-7834 (Shin CY), +82-2-958-8556 (GH Bahn)
Fax: +82-2-2049-7899 (Shin CY), +82-2-957-1997 (GH Bahn)
ψPresent Address
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
The first three authors contributed equally to this work.
Received: November 1, 2016; Revised: November 24, 2016; Accepted: December 6, 2016; Published online: February 17, 2017.
© The Korean Society of Applied Pharmacology. All rights reserved.

Abstract
Autism spectrum disorder (ASD) remains unexplained and untreated despite the high attention of research in recent years. Aside from its various characteristics is the baffling male preponderance over the female population. Using a validated animal model of ASD which is the telomerase reverse transcriptase overexpressing mice (TERT-tg), we conducted ASD-related behavioral assessments and protein expression experiments to mark the difference between male and females of this animal model. After statistically analyzing the results, we found significant effects of TERT overexpression in sociability, social novelty preference, anxiety, nest building, and electroseizure threshold in the males but not their female littermates. Along these differences are the male-specific increased expressions of postsynaptic proteins which are the NMDA and AMPA receptors in the prefrontal cortex. The vGluT1 presynaptic proteins, but not GAD, were upregulated in both sexes of TERT-tg mice, although it is more significantly pronounced in the male group. Here, we confirmed that the behavioral effect of TERT overexpression in mice was male-specific, suggesting that the aberration of this gene and its downstream pathways preferentially affect the functional development of the male brain, consistent with the male preponderance in ASD.
Keywords: Sex difference, TERT transgenic mice, Autism spectrum disorder, Synapse, Excitatory/Inhibitory imbalance


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