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-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.