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Pax6-Dependent Cortical Glutamatergic Neuronal Differentiation Regulates Autism-Like Behavior in Prenatally Valproic Acid-Exposed Rat Offspring

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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.

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Acknowledgments

This work was supported by Mid-career Researcher Program (2011–0014258) and the framework of international cooperation program (2012K2A1A2032549) through the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST).

Conflict of Interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmacology, College of Pharmacy, Seoul National University, Seoul, South Korea

    Ki Chan Kim & Hyo Sang Go

  2. Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Konkuk University, Seoul, South Korea

    Ki Chan Kim, Hyo Sang Go, Pitna Kim, Chang Soon Choi, Ji-Woon Kim & Chan Young Shin

  3. School of Life Sciences, Bioimaging Research Center and Cell Dynamics Research Center, Gwangju Institute of Science and Technology, Oryong-dong, Buk-gu, Gwangju, 500-712, South Korea

    Dong-Keun Lee & Mi-Ryoung Song

  4. Department of Pharmacology, School of Medicine, Konkuk University, 1 Hwayang-Dong, Kwangjin-Gu, Seoul, 143-701, South Korea

    Pitna Kim, Chang Soon Choi, Ji-Woon Kim & Chan Young Shin

  5. Department of Psychiatry, School of Medicine, University of California, Los Angeles, CA, 90095, USA

    Se Jin Jeon

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  1. Ki Chan Kim
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  2. Dong-Keun Lee
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  3. Hyo Sang Go
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  4. Pitna Kim
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  5. Chang Soon Choi
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  6. Ji-Woon Kim
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  7. Se Jin Jeon
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  8. Mi-Ryoung Song
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  9. Chan Young Shin
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Corresponding authors

Correspondence to Mi-Ryoung Song or Chan Young Shin.

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Kim, K.C., Lee, DK., Go, H.S. et al. Pax6-Dependent Cortical Glutamatergic Neuronal Differentiation Regulates Autism-Like Behavior in Prenatally Valproic Acid-Exposed Rat Offspring. Mol Neurobiol 49, 512–528 (2014). https://doi.org/10.1007/s12035-013-8535-2

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  • DOI: https://doi.org/10.1007/s12035-013-8535-2

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