Estrogen treatment reverses prematurity-induced disruption in cortical interneuron population

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 + , somatostatin + , calretinin + , and neuropeptide-Y + 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 parvalbumin + and calretinin + neurons were abundant, whereas somatostatin + and neuropeptide-Y + neurons were few in cortical layers of human infants. Premature birth of infants reduced the density of parvalbumin + or GAD67 + neurons and increased somatostatin + interneurons in the upper cortical layers. Importantly, 17-β-estradiol treatment in preterm rabbits increased the number of parvalbumin + neurons in the upper cortical layers relative to controls at postnatal days 14 and 21, and transiently reduced somatostatin population at day 14. 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. Hence, deficits in parvalbumin + and excess of somatostatin + neurons in premature newborns is ameliorated by estrogen-replacement, which can be attributed to elevated Arx levels. Estrogen-replacement might enhance neurodevelopmental outcomes in extremely preterm infants. Significance Premature-birth often leads to neurodevelopmental delays and behavioral disorders, which may be ascribed to disturbances in the development and maturation of cortical interneurons. Here, we show that preterm-birth in humans is associated with reduced population of parvalbumin + neurons and an excess of somatostatin-expressing interneurons in the cerebral cortex. More importantly, 17-β-estradiol treatment increased the number of parvalbumin + neurons in preterm-born rabbits, which appears to be mediated by an elevation in the expression of Arx transcription factor. Hence, the present study highlights prematurity-induced reduction in parvalbumin + neurons in human infants and reversal in their population by estrogen-replacement in preterm rabbits. As preterm-birth drops plasma estrogen level 100 fold, estrogen-replacement in extremely preterm infants might improve their developmental outcome and minimize neurobehavioral disorders.