Maternal separation attenuates the capacity of adult neural precursors to differentiate into neurons via methylation of RARα

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  • Boku Shuken
    Department of Psychiatry, Kobe University Graduate School of Medicine

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  • 母子分離ストレスは RARα遺伝子のメチル化増加を介して成体海馬神経前駆細胞の分化能を減弱させる
  • ボシ ブンリ ストレス ワ RARaイデンシ ノ メチルカ ゾウカ オ カイシテ セイタイ カイバ シンケイ ゼンク サイボウ ノ ブンカノウ オ ゲン ヨワサセル

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Abstract

Early-life stress affects brain development and contributes to psychiatric disorders. Adult neurogenesis in the dentate gyrus (DG) is also involved in psychiatric disorders and early-life stress decreases adult neurogenesis in DG. These suggest that early-life stress might contribute to psychiatric disorders via adult neurogenesis in DG. Here we examined the effects of maternal separation (MS) in early-life on adult rat DG-derived neural precursors (ADP) . In MS group, pups were separated from mothers for 3 hours daily from postnatal day (PND) 2 to 14. At PND 56, ADP were isolated from both groups. Effects of MS on ADP were examined with immunocytochemistry. An epigenetic mechanism underlying them was investigated with DNA methyltransferase inhibitor (DNMT-i) . MS attenuated ADP differentiation into neuron. DNMT-i recovered MS-attenuated neural differentiation. MS decreased DNMT1 expression. These suggest that MS-increased DNA methylation might be involved in MS-attenuated ADP neural differentiation. Next, we focused on RARα as a candidate gene in which DNA methylation is altered by MS. MS decreased RARα expression. RARα agonist and antagonist reciprocally affected neural differentiation. DNMT-i recovered MS-decreased RARα expression. MS increased DNA methylation in RARαpromoter. Therefore, MS may attenuate ADP neural differentiation via increasing DNMT1 expression and DNA methylation in RARα promoter.

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