Disruption of interneuron neurogenesis in premature newborns and reversal with Estrogen treatment

Mahima Tibrewal, Bokun Cheng, Preeti Dohare, Furong Hu, Rana Mehdizadeh, Ping Wang, Deyou Zheng, Zoltan Ungvari, Praveen Ballabh

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Many 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 that restoration of the hypoxic milieu or estrogen treatment might reverse interneuron generation. To test these hypotheses, we compared interneuronal progenitors in the medial ganglionic eminences (MGEs), lateral ganglionic eminences (LGEs), and caudal ganglionic eminences (CGEs) between preterm-born [born on embryonic day (E) 29; examined on postnatal day (D) 3 and D7] and term-born (born on E32; examined on D0 and D4) rabbits at equivalent postconceptional ages.Wefound that both total and cycling Nkx2.1+, Dlx2+, and Sox2+ cells were more abundant in the MGEs of preterm rabbits at D3 compared with term rabbits at D0, but not in D7 preterm relative to D4 term pups. Total Nkx2.1+ progenitors were also more numerous in the LGEs of preterm pups at D3 compared with term rabbits at D0. Dlx2+ cells in CGEs 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 MGEs and enhanced Ascl1 transcription factor. Estrogen treatment also reduced Ki67, c-Myc, and phosphorylation of retinoblastoma protein, suggesting 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.

Original languageEnglish (US)
Pages (from-to)1100-1113
Number of pages14
JournalJournal of Neuroscience
Volume38
Issue number5
DOIs
StatePublished - Jan 31 2018

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Keywords

  • Estrogen
  • Interneuron
  • Medial ganglionic eminence
  • Neurogenesis
  • Nkx2.1
  • Premature rabbits

ASJC Scopus subject areas

  • Neuroscience(all)

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