TY - JOUR
T1 - Neonatal maternal separation alters the capacity of adult neural precursor cells to differentiate into neurons via methylation of retinoic acid receptor gene promoter
AU - Boku, Shuken
AU - Toda, Hiroyuki
AU - Nakagawa, Shin
AU - Kato, Akiko
AU - Inoue, Takeshi
AU - Koyama, Tsukasa
AU - Hiroi, Noboru
AU - Kusumi, Ichiro
N1 - Funding Information:
This work was supported in part by a grant-in-aid No. 18591269 for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan , and by a grant from SENSHIN Medical Research Foundation, Japan , to SB and a National Institutes of Health grant ( MH099660 ) to NH.
PY - 2015
Y1 - 2015
N2 - BACKGROUND: Early life stress is thought to contribute to psychiatric disorders, but the precise mechanisms underlying this link are poorly understood. As neonatal stress decreases adult hippocampal neurogenesis, which, in turn, functionally contributes to many behavioral phenotypes relevant to psychiatric disorders, we examined how in vivo neonatal maternal separation (NMS) impacts the capacity of adult hippocampal neural precursor cells via epigenetic alterations in vitro. METHODS: Rat pups were separated from their dams for 3 hours daily from postnatal day (PND) 2 to PND 14 or were never separated from the dam (as control animals). We isolated adult neural precursor cells from the hippocampal dentate gyrus at PND 56 and assessed rates of proliferation, apoptosis, and differentiation in cell culture. We also evaluated the effect of DNA methylation at the retinoic acid receptor (RAR) promoter stemming from NMS on adult neural precursor cells. RESULTS: NMS attenuated neural differentiation of adult neural precursor cells but had no detectible effect on proliferation, apoptosis, or astroglial differentiation. The DNA methyltransferase (DNMT) inhibitor, 5-aza-dC, reversed a reduction by NMS of neural differentiation of adult neural precursor cells. NMS increased DNMT1 expression and decreased expression of RARα. An RARα agonist increased neural differentiation and an antagonist reduced retinoic acid-induced neural differentiation. NMS increased the methylated portion of RARα promoter, and the DNMT inhibitor reversed a reduction by NMS of RARα messenger RNA expression. CONCLUSIONS: NMS attenuates the capacity of adult hippocampal neural precursor cells to differentiate into neurons by decreasing expression of RARα through DNMT1-mediated methylation of its promoter.
AB - BACKGROUND: Early life stress is thought to contribute to psychiatric disorders, but the precise mechanisms underlying this link are poorly understood. As neonatal stress decreases adult hippocampal neurogenesis, which, in turn, functionally contributes to many behavioral phenotypes relevant to psychiatric disorders, we examined how in vivo neonatal maternal separation (NMS) impacts the capacity of adult hippocampal neural precursor cells via epigenetic alterations in vitro. METHODS: Rat pups were separated from their dams for 3 hours daily from postnatal day (PND) 2 to PND 14 or were never separated from the dam (as control animals). We isolated adult neural precursor cells from the hippocampal dentate gyrus at PND 56 and assessed rates of proliferation, apoptosis, and differentiation in cell culture. We also evaluated the effect of DNA methylation at the retinoic acid receptor (RAR) promoter stemming from NMS on adult neural precursor cells. RESULTS: NMS attenuated neural differentiation of adult neural precursor cells but had no detectible effect on proliferation, apoptosis, or astroglial differentiation. The DNA methyltransferase (DNMT) inhibitor, 5-aza-dC, reversed a reduction by NMS of neural differentiation of adult neural precursor cells. NMS increased DNMT1 expression and decreased expression of RARα. An RARα agonist increased neural differentiation and an antagonist reduced retinoic acid-induced neural differentiation. NMS increased the methylated portion of RARα promoter, and the DNMT inhibitor reversed a reduction by NMS of RARα messenger RNA expression. CONCLUSIONS: NMS attenuates the capacity of adult hippocampal neural precursor cells to differentiate into neurons by decreasing expression of RARα through DNMT1-mediated methylation of its promoter.
KW - Adult neurogenesis
KW - Dentate gyrus
KW - Dna methylation
KW - Dna methyltransferase
KW - Maternal separation
KW - Retinoic acid receptor
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U2 - 10.1016/j.biopsych.2014.07.008
DO - 10.1016/j.biopsych.2014.07.008
M3 - Article
C2 - 25127741
AN - SCOPUS:84922583187
SN - 0006-3223
VL - 77
SP - 335
EP - 344
JO - Biological Psychiatry
JF - Biological Psychiatry
IS - 4
ER -