title: Prenatal exposure to valproic acid increases the neural progenitor cell pool and induces macrocephaly in rat brain via a mechanism involving the GSK-3β/β-catenin pathway.
abstract: Autism is a spectrum of neurodevelopmental disorders characterized by social isolation and lack of interaction. Anatomically, autism patients often show macrocephaly and high neuronal density. To investigate the mechanism underlying the higher neuronal populations seen in ASD, we subcutaneously injected VPA (400 mg/kg) into pregnant Sprague-Dawley rats on E12, an animal model often used in ASD study. Alternatively, cultured rat neural progenitor cells were treated with VPA. Until E18, VPA induced NPC proliferation and delayed neurogenesis in fetal brain, but the subsequent differentiation of NPCs to neurons increased brain neuronal density afterward. Similar findings were observed with NPCs treated with VPA in vitro. At a molecular level, VPA enhanced Wnt1 expression and activated the GSK-3β/β-catenin pathway. Furthermore, inhibition of this pathway attenuated the effects of VPA. The findings of this study suggest that an altered developmental process underlies the macrocephaly and abnormal brain structure observed in the autistic brain.
authors: Department of Pharmacology, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
authors: Hyo Sang
authors: HS
authors: Go
authors: Ki Chan
authors: KC
authors: Kim
authors: Chang Soon
authors: CS
authors: Choi
authors: Se Jin
authors: SJ
authors: Jeon
authors: Kyung Ja
authors: KJ
authors: Kwon
authors: Seol-Heui
authors: SH
authors: Han
authors: Jongmin
authors: J
authors: Lee
authors: Jae Hoon
authors: JH
authors: Cheong
authors: Jong Hoon
authors: JH
authors: Ryu
authors: Chong-Hyun
authors: CH
authors: Kim
authors: Kwang Ho
authors: KH
authors: Ko
authors: Chan Young
authors: CY
authors: Shin
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D000963:Antimetabolites; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004396:Coloring Agents; D005260:Female; D005434:Flow Cytometry; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry; D058627:Megalencephaly / Q000139:chemically induced* / Q000473:pathology; D058953:Neural Stem Cells / Q000187:drug effects*; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013778:Tetrazolium Salts; D013844:Thiazoles; D014162:Transfection; D014635:Valproic Acid / Q000633:toxicity*; D051176:beta Catenin / Q000235:genetics / Q000502:physiology*
chemical_list: D000927:Anticonvulsants; D000963:Antimetabolites; D004396:Coloring Agents; D013778:Tetrazolium Salts; D013844:Thiazoles; D051176:beta Catenin; D014635:Valproic Acid; D038362:Glycogen Synthase Kinase 3; C022616:thiazolyl blue; D001973:Bromodeoxyuridine