Neurosteroid therapy prevents neurodevelopmental deficits to the dopamine pathway and myelination following preterm birth

Preterm birth is associated with an increased risk of neurodevelopmental deficits. Specifically, preterm-born infants have an increased likelihood of developing neurobehavioural disorders, in particular attention deficit hyperactivity disorder (ADHD). This disorder is underpinned by dysregulation of dopamine; however, knowledge of how preterm birth affects this pathway is limited. When infants are born preterm, they prematurely lose the support of the placentally derived neurosteroid, allopregnanolone. This neurosteroid is critical for brain development in the last trimester particularly, as it increases protective inhibition which is vital for processes such as myelination to develop appropriately. Following this premature loss with preterm birth, we hypothesise that there will be an increase in excitotoxic damage to the brain, which will disrupt the dopamine pathway, myelination, and subsequently cause behavioural abnormalities. We further hypothesise that treatment with neurosteroid therapies, both in vitro and in vivo, will prevent these disruptions from occurring. Using a guinea pig model, we found that preterm birth causes long lasting disruptions to key components of the dopaminergic and noradrenergic pathways, which may be related to the behavioural abnormalities observed. Disruption to these pathways occurred in a sex specific manner, which may explain the sex differences in the development of these disorders. To further investigate these mechanisms, we developed a novel primary cell culture model using guinea pig frontal cortex tissue to examine impacts directly on isolated neurons and oligodendrocytes. Using this model, we exposed the cells to oxygen-glucose deprivation (OGD) as a model of preterm birth insult and examined the effects of two neuroprotective neurosteroid treatments; zuranolone and etifoxine. Zuranolone displayed the most robust neuroprotective effects on the cells, and thus was utilised in the preterm caesarean-section in vivo model of preterm birth. Preterm pups were treated with zuranolone in the immediate postnatal period up until term equivalence. Preterm birth induced deficits in the dopaminergic pathway, myelination and behaviour were again observed in late childhood equivalence, however, treatment with zuranolone ameliorated a range of these deficits. To conclude, we uncovered disruptions to the dopamine pathway that may contribute to the myelination deficits and hyperactivity seen following preterm birth and identified a neurosteroid based therapy that promoted healthy neurodevelopment and prevented the onset of neurobehavioural disorders following preterm birth.