PT  - JOURNAL ARTICLE
AU  - Mahima Tibrewal
AU  - Bokun Cheng
AU  - Preeti Dohare
AU  - Furong Hu
AU  - Rana Mehdizadeh
AU  - Ping Wang
AU  - Deyou Zheng
AU  - Zoltan Ungvari
AU  - Praveen Ballabh
TI  - Disruption of Interneuron Neurogenesis in Premature Newborns and Reversal with Estrogen Treatment
AID  - 10.1523/JNEUROSCI.1875-17.2017
DP  - 2017 Dec 15
TA  - The Journal of Neuroscience
PG  - 1875-17
4099  - http://www.jneurosci.org/content/early/2017/12/15/JNEUROSCI.1875-17.2017.short
4100  - http://www.jneurosci.org/content/early/2017/12/15/JNEUROSCI.1875-17.2017.full
AB  - Preterm-born children suffer from neurobehavioral disorders. Premature birth terminates the hypoxic in utero environment and supply of maternal hormones. As the production of interneurons continues until the end of pregnancy, we hypothesized that premature birth would disrupt interneuron production and restoration of the hypoxic milieu or estrogen treatment might reverse interneuron generation. To test these hypotheses, we quantified interneuronal progenitors in the medial, lateral, and caudal ganglionic eminences (MGE, LGE, and CGE) of preterm- (E29 at D3 and D7) vs. term-born (E32 at D0 and D4) rabbits at equivalent postconceptional ages. We found that both total and cycling Nkx2.1+, Dlx2+, and Sox2+ cells were more abundant in the MGE of preterm rabbits at D3 compared to term rabbits at D0, but not in D7 preterm relative to D4 term pups. Total Nkx2.1+ progenitors were also more numerous in the LGE of preterm pups at D3 compared to term rabbits at D0. Dlx2+ cells in CGE were comparable between preterm and term pups. Simulation of hypoxia by dimethyloxalylglycine treatment did not affect the number of interneuronal progenitors. However, estrogen treatment reduced the density of total and proliferating Nkx2.1+ and Dlx2+ cells in the MGE and enhanced Ascl1 transcription factor. Estrogen treatment also reduced Ki67, c-Myc, and phosphorylation of retinoblastoma protein, suggesting an inhibition of the G1-to-S phase transition. Hence, preterm birth disrupts interneuron neurogenesis in the MGE and estrogen treatment reverses interneuron neurogenesis in preterm newborns by cell cycle inhibition and elevation of Ascl1. We speculate that estrogen replacement might partially restore neurogenesis in human premature infants.SignificancePrematurity results in developmental delays and neurobehavioral disorders, which may be ascribed to disturbances in the development and maturation of cortical interneurons. Here, we show that preterm birth disrupts interneuron neurogenesis in the MGE, and more importantly, estrogen treatment reverses the disturbance in the population of interneuron progenitors in the MGE. The effect of estrogen is mediated by inhibition of the cell cycle and elevation in Ascl1 expression. As preterm birth drops plasma estrogen level 100 fold, the estrogen replacement in preterm birth is physiological. We speculate that estrogen-replacement in extremely preterm infants might partially restore neurogenesis in human premature infants.