title: MeCP2 Modulates Sex Differences in the Postsynaptic Development of the Valproate Animal Model of Autism.
abstract: Males are predominantly affected by autism spectrum disorders (ASD) with a prevalence ratio of 5:1. However, the underlying pathological mechanisms governing the male preponderance of ASD remain unclear. Recent studies suggested that epigenetic aberrations may cause synaptic dysfunctions, which might be related to the pathophysiology of ASD. In this study, we used rat offspring prenatally exposed to valproic acid (VPA) as an animal model of ASD. We found male-selective abnormalities in the kinetic profile of the excitatory glutamatergic synaptic protein expressions linked to N-methyl-D-aspartate receptor (NMDAR), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and metabotropic glutamate receptor 5 (mGluR5) pathways in the prefrontal cortex of the VPA-exposed offspring at postnatal weeks 1, 2, and 4. Furthermore, VPA exposure showed a male-specific attenuation of the methyl-CpG-binding protein 2 (MeCP2) expressions both in the prefrontal cortex of offspring and in the gender-isolated neural progenitor cells (NPCs). In the gender-isolated NPCs culture, higher concentration of VPA induced an increased glutamatergic synaptic development along with decreased MeCP2 expression in both genders suggesting the role of MeCP2 in the modulation of synaptic development. In the small interfering RNA (siRNA) knock-down study, 50 pmol of Mecp2 siRNA inhibited the MeCP2 expression in male- but not in female-derived NPCs with concomitant induction of postsynaptic proteins such as PSD95. Taken together, we suggest that the male-inclined reduction of MeCP2 expression is involved in the abnormal development of glutamatergic synapse and male preponderance in the VPA animal models of ASD.
authors.affiliation: Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Konkuk University, Seoul, South Korea.|Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
authors.forename: Ki Chan
authors.initials: KC
authors.lastname: Kim
authors.affiliation: Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Konkuk University, Seoul, South Korea.|KU Open Innovation Center, Konkuk University, Seoul, South Korea.|Department of Neuroscience, School of Medicine, 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.|KU Open Innovation Center, Konkuk University, Seoul, South Korea.|Department of Neuroscience, School of Medicine, Konkuk University, Seoul, South Korea.
authors.forename: Ji-Woon
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Konkuk University, Seoul, South Korea.
authors.forename: Seol-Heui
authors.initials: SH
authors.lastname: Han
authors.affiliation: Department of Pharmacology, College of Pharmacy, Sahmyook University, Seoul, South Korea.
authors.forename: Jae Hoon
authors.initials: JH
authors.lastname: Cheong
authors.affiliation: Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, South Korea.
authors.forename: Jong Hoon
authors.initials: JH
authors.lastname: Ryu
authors.affiliation: Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Konkuk University, Seoul, South Korea. chanyshin@kku.ac.kr.|KU Open Innovation Center, Konkuk University, Seoul, South Korea. chanyshin@kku.ac.kr.|Department of Neuroscience, School of Medicine, 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 / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism* / Q000473:pathology; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012727:Sex Characteristics; D013569:Synapses / Q000378:metabolism*; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D051783:Methyl-CpG-Binding Protein 2; D016194:Receptors, N-Methyl-D-Aspartate; D014635:Valproic Acid
keywords: Autism spectrum disorders; Gender differences; Glutamatergic synapse; MeCP2; Valproic acid