Estrogen treatment reverses prematurity-induced disruption in cortical interneuron population

Sanjeet Panda, Preeti Dohare, Samhita Jain, Nirzar Parikh, Pranav Singla, Rana Mehdizadeh, Damon W. Klebe, George M. Kleinman, Bokun Cheng, Praveen Ballabh

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Development of cortical interneurons continues until the end of human pregnancy. Premature birth deprives the newborns from the supply of maternal estrogen and a secure intrauterine environment. Indeed, preterm infants suffer from neurobehavioral disorders. This can result from both preterm birth and associated postnatal complications, which might disrupt recruitment and maturation of cortical interneurons. We hypothesized that interneuron subtypes, including parvalbumin-positive (PV+), somatostatin-positive (SST+), calretinin-positive (CalR+), and neuropeptide Y-positive (NPY+) interneurons, were recruited in the upper and lower cortical layers in a distinct manner with advancing gestational age. In addition, preterm birth would disrupt the heterogeneity of cortical interneurons, which might be reversed by estrogen treatment. These hypotheses were tested by analyzing autopsy samples from premature infants and evaluating the effect of estrogen supplementation in prematurely delivered rabbits. The PV+ and CalR+ neurons were abundant, whereas SST+ and NPY+ neurons were few in cortical layers of preterm human infants. Premature birth of infants reduced the density of PV+ or GAD67+ neurons and increased SST+ interneurons in the upper cortical layers. Importantly, 17 β-estradiol treatment in preterm rabbits increased the number of PV+ neurons in the upper cortical layers relative to controls at postnatal day 14 (P14) and P21 and transiently reduced SST population at P14. Moreover, protein and mRNA levels of Arx, a key regulator of cortical interneuron maturation and migration, were higher in estrogen-treated rabbits relative to controls. Therefore, deficits in PV+ and excess of SST+ neurons in premature newborns are ameliorated by estrogen replacement, which can be attributed to elevated Arx levels. Estrogen replacement might enhance neurodevelopmental outcomes in extremely preterm infants.

Original languageEnglish (US)
Pages (from-to)7378-7391
Number of pages14
JournalJournal of Neuroscience
Volume38
Issue number34
DOIs
StatePublished - Aug 22 2018

Fingerprint

Interneurons
Estrogens
Premature Birth
Premature Infants
Neurons
Population
Estrogen Replacement Therapy
Rabbits
Therapeutics
Extremely Premature Infants
Newborn Infant
Calbindin 2
Parvalbumins
Neuropeptide Y
Somatostatin
Gestational Age
Autopsy
Estradiol
Mothers
Pregnancy

Keywords

  • Arx
  • Cerebral cortex
  • Estrogen
  • Interneuron
  • Parvalbumin
  • Somatostatin

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Estrogen treatment reverses prematurity-induced disruption in cortical interneuron population. / Panda, Sanjeet; Dohare, Preeti; Jain, Samhita; Parikh, Nirzar; Singla, Pranav; Mehdizadeh, Rana; Klebe, Damon W.; Kleinman, George M.; Cheng, Bokun; Ballabh, Praveen.

In: Journal of Neuroscience, Vol. 38, No. 34, 22.08.2018, p. 7378-7391.

Research output: Contribution to journalArticle

Panda, S, Dohare, P, Jain, S, Parikh, N, Singla, P, Mehdizadeh, R, Klebe, DW, Kleinman, GM, Cheng, B & Ballabh, P 2018, 'Estrogen treatment reverses prematurity-induced disruption in cortical interneuron population', Journal of Neuroscience, vol. 38, no. 34, pp. 7378-7391. https://doi.org/10.1523/JNEUROSCI.0478-18.2018
Panda, Sanjeet ; Dohare, Preeti ; Jain, Samhita ; Parikh, Nirzar ; Singla, Pranav ; Mehdizadeh, Rana ; Klebe, Damon W. ; Kleinman, George M. ; Cheng, Bokun ; Ballabh, Praveen. / Estrogen treatment reverses prematurity-induced disruption in cortical interneuron population. In: Journal of Neuroscience. 2018 ; Vol. 38, No. 34. pp. 7378-7391.
@article{88a91f1b29ac4efa861157cf742042f8,
title = "Estrogen treatment reverses prematurity-induced disruption in cortical interneuron population",
abstract = "Development of cortical interneurons continues until the end of human pregnancy. Premature birth deprives the newborns from the supply of maternal estrogen and a secure intrauterine environment. Indeed, preterm infants suffer from neurobehavioral disorders. This can result from both preterm birth and associated postnatal complications, which might disrupt recruitment and maturation of cortical interneurons. We hypothesized that interneuron subtypes, including parvalbumin-positive (PV+), somatostatin-positive (SST+), calretinin-positive (CalR+), and neuropeptide Y-positive (NPY+) interneurons, were recruited in the upper and lower cortical layers in a distinct manner with advancing gestational age. In addition, preterm birth would disrupt the heterogeneity of cortical interneurons, which might be reversed by estrogen treatment. These hypotheses were tested by analyzing autopsy samples from premature infants and evaluating the effect of estrogen supplementation in prematurely delivered rabbits. The PV+ and CalR+ neurons were abundant, whereas SST+ and NPY+ neurons were few in cortical layers of preterm human infants. Premature birth of infants reduced the density of PV+ or GAD67+ neurons and increased SST+ interneurons in the upper cortical layers. Importantly, 17 β-estradiol treatment in preterm rabbits increased the number of PV+ neurons in the upper cortical layers relative to controls at postnatal day 14 (P14) and P21 and transiently reduced SST population at P14. Moreover, protein and mRNA levels of Arx, a key regulator of cortical interneuron maturation and migration, were higher in estrogen-treated rabbits relative to controls. Therefore, deficits in PV+ and excess of SST+ neurons in premature newborns are ameliorated by estrogen replacement, which can be attributed to elevated Arx levels. Estrogen replacement might enhance neurodevelopmental outcomes in extremely preterm infants.",
keywords = "Arx, Cerebral cortex, Estrogen, Interneuron, Parvalbumin, Somatostatin",
author = "Sanjeet Panda and Preeti Dohare and Samhita Jain and Nirzar Parikh and Pranav Singla and Rana Mehdizadeh and Klebe, {Damon W.} and Kleinman, {George M.} and Bokun Cheng and Praveen Ballabh",
year = "2018",
month = "8",
day = "22",
doi = "10.1523/JNEUROSCI.0478-18.2018",
language = "English (US)",
volume = "38",
pages = "7378--7391",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "34",

}

TY - JOUR

T1 - Estrogen treatment reverses prematurity-induced disruption in cortical interneuron population

AU - Panda, Sanjeet

AU - Dohare, Preeti

AU - Jain, Samhita

AU - Parikh, Nirzar

AU - Singla, Pranav

AU - Mehdizadeh, Rana

AU - Klebe, Damon W.

AU - Kleinman, George M.

AU - Cheng, Bokun

AU - Ballabh, Praveen

PY - 2018/8/22

Y1 - 2018/8/22

N2 - Development of cortical interneurons continues until the end of human pregnancy. Premature birth deprives the newborns from the supply of maternal estrogen and a secure intrauterine environment. Indeed, preterm infants suffer from neurobehavioral disorders. This can result from both preterm birth and associated postnatal complications, which might disrupt recruitment and maturation of cortical interneurons. We hypothesized that interneuron subtypes, including parvalbumin-positive (PV+), somatostatin-positive (SST+), calretinin-positive (CalR+), and neuropeptide Y-positive (NPY+) interneurons, were recruited in the upper and lower cortical layers in a distinct manner with advancing gestational age. In addition, preterm birth would disrupt the heterogeneity of cortical interneurons, which might be reversed by estrogen treatment. These hypotheses were tested by analyzing autopsy samples from premature infants and evaluating the effect of estrogen supplementation in prematurely delivered rabbits. The PV+ and CalR+ neurons were abundant, whereas SST+ and NPY+ neurons were few in cortical layers of preterm human infants. Premature birth of infants reduced the density of PV+ or GAD67+ neurons and increased SST+ interneurons in the upper cortical layers. Importantly, 17 β-estradiol treatment in preterm rabbits increased the number of PV+ neurons in the upper cortical layers relative to controls at postnatal day 14 (P14) and P21 and transiently reduced SST population at P14. Moreover, protein and mRNA levels of Arx, a key regulator of cortical interneuron maturation and migration, were higher in estrogen-treated rabbits relative to controls. Therefore, deficits in PV+ and excess of SST+ neurons in premature newborns are ameliorated by estrogen replacement, which can be attributed to elevated Arx levels. Estrogen replacement might enhance neurodevelopmental outcomes in extremely preterm infants.

AB - Development of cortical interneurons continues until the end of human pregnancy. Premature birth deprives the newborns from the supply of maternal estrogen and a secure intrauterine environment. Indeed, preterm infants suffer from neurobehavioral disorders. This can result from both preterm birth and associated postnatal complications, which might disrupt recruitment and maturation of cortical interneurons. We hypothesized that interneuron subtypes, including parvalbumin-positive (PV+), somatostatin-positive (SST+), calretinin-positive (CalR+), and neuropeptide Y-positive (NPY+) interneurons, were recruited in the upper and lower cortical layers in a distinct manner with advancing gestational age. In addition, preterm birth would disrupt the heterogeneity of cortical interneurons, which might be reversed by estrogen treatment. These hypotheses were tested by analyzing autopsy samples from premature infants and evaluating the effect of estrogen supplementation in prematurely delivered rabbits. The PV+ and CalR+ neurons were abundant, whereas SST+ and NPY+ neurons were few in cortical layers of preterm human infants. Premature birth of infants reduced the density of PV+ or GAD67+ neurons and increased SST+ interneurons in the upper cortical layers. Importantly, 17 β-estradiol treatment in preterm rabbits increased the number of PV+ neurons in the upper cortical layers relative to controls at postnatal day 14 (P14) and P21 and transiently reduced SST population at P14. Moreover, protein and mRNA levels of Arx, a key regulator of cortical interneuron maturation and migration, were higher in estrogen-treated rabbits relative to controls. Therefore, deficits in PV+ and excess of SST+ neurons in premature newborns are ameliorated by estrogen replacement, which can be attributed to elevated Arx levels. Estrogen replacement might enhance neurodevelopmental outcomes in extremely preterm infants.

KW - Arx

KW - Cerebral cortex

KW - Estrogen

KW - Interneuron

KW - Parvalbumin

KW - Somatostatin

UR - http://www.scopus.com/inward/record.url?scp=85052221017&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85052221017&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.0478-18.2018

DO - 10.1523/JNEUROSCI.0478-18.2018

M3 - Article

C2 - 30037831

AN - SCOPUS:85052221017

VL - 38

SP - 7378

EP - 7391

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 34

ER -