title: Pax6-dependent cortical glutamatergic neuronal differentiation regulates autism-like behavior in prenatally valproic acid-exposed rat offspring.
abstract: Imbalance in excitatory/inhibitory signal in the brain has been proposed as one of the main pathological features in autism spectrum disorders, although the underlying cellular and molecular mechanism is unclear yet. Because excitatory/inhibitory imbalance can be induced by aberration in glutamatergic/GABAergic neuronal differentiation, we investigated the mechanism of dysregulated neuronal differentiation between excitatory and inhibitory neurons in the embryonic and postnatal brain of prenatally valproic acid-exposed rat offspring, which is often used as an animal model of autism spectrum disorders. Transcription factor Pax6, implicated in glutamatergic neuronal differentiation, was transiently increased in embryonic cortex by valproate exposure, which resulted in the increased expression of glutamatergic proteins in postnatal brain of offspring. Chromatin immunoprecipitation showed increased acetylated histone binding on Pax6 promoter region, which may underlie the transcriptional up-regulation of Pax6. Other histone deacetylase (HDAC) inhibitors including TSA and SB but not valpromide, which is devoid of HDAC inhibitor activity, induced Pax6 up-regulation. Silencing Pax6 expression in cultured rat primary neural progenitor cells demonstrated that up-regulation of Pax6 plays an essential role in valproate-induced glutamatergic differentiation. Blocking glutamatergic transmission with MK-801 or memantine treatment, and to a lesser extent with MPEP treatment, reversed the impaired social behaviors and seizure susceptibility of prenatally valproate-exposed offspring. Together, environmental factors may contribute to the imbalance in excitatory/inhibitory neuronal activity in autistic brain by altering expression of transcription factors governing glutamatergic/GABAergic differentiation during fetal neural development, in conjunction with the genetic preload.
authors.affiliation: Department of Pharmacology, College of Pharmacy, Seoul National University, Seoul, South Korea.
authors.forename: Ki Chan
authors.initials: KC
authors.lastname: Kim
authors.forename: Dong-Keun
authors.initials: DK
authors.lastname: Lee
authors.forename: Hyo Sang
authors.initials: HS
authors.lastname: Go
authors.forename: Pitna
authors.initials: P
authors.lastname: Kim
authors.forename: Chang Soon
authors.initials: CS
authors.lastname: Choi
authors.forename: Ji-Woon
authors.initials: JW
authors.lastname: Kim
authors.forename: Se Jin
authors.initials: SJ
authors.lastname: Jeon
authors.forename: Mi-Ryoung
authors.initials: MR
authors.lastname: Song
authors.forename: Chan Young
authors.initials: CY
authors.lastname: Shin
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005136:Eye Proteins / Q000096:biosynthesis / Q000502:physiology*; D005260:Female; D018698:Glutamic Acid / Q000502:physiology*; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000502:physiology*; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000096:biosynthesis / Q000502:physiology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D012097:Repressor Proteins / Q000096:biosynthesis / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology; D014635:Valproic Acid / Q000633:toxicity*
chemical_list: D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C000605733:Pax6 protein, rat; D012097:Repressor Proteins; D018698:Glutamic Acid; D014635:Valproic Acid
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