Neurodevelopmental impacts of neurosteroid and excitatory/inhibitory modulation on the cerebellum following preterm birth associated insults

Preterm birth causes impaired cerebellar development which is associated with an increased prevalence for developing neurobehavioral disorders such as attention deficit hyperactivity disorder (ADHD) and anxiety. Preterm birth exposes the neonate to the harsh ex utero environment, causing hypoxic-ischemic insults which are magnified by premature loss of placentally derived, inhibitory neurosteroids, which are critical for optimal neurodevelopment. Hypoxic-ischemic insult and reduced inhibitory tone promote excitotoxic events which the excitatory synapse dense, developing, cerebellum is especially vulnerable to. We hypothesise that preterm birth associated insults disrupt GABAergic and glutamatergic pathways causing impaired oligodendrocyte maturation and myelination which ultimately leads to the development of neurobehavioral pathology. It is further hypothesised that excitation modulating compounds administered as neurosteroid replacement therapy, in the immediate neonatal period, will demonstrate neuroprotective effects and restore a term born phenotype. In a guinea pig model of induced preterm birth, it was found that GABAergic and glutamatergic pathway expression was impaired and oligodendrocyte maturation and myelination were disrupted in a sexually dimorphic manner, resulting in a hyperactive phenotype, more markedly in neonatal males. Neurosteroid replacement therapy using ganaxolone was found to protect against impairments in both sexes. A novel primary guinea pig cerebellar neuron culture was developed to allow for rapid, cost-effective, multi-drug investigations for treating hypoxic-ischemic insults associated with preterm births. Oxygen-glucose deprivation (OGD), used to model hypoxic-ischemic insult, resulted in sex specific impairments of inhibitory/excitatory pathway expression. Importantly, excitation modulating compounds, in OGD conditions, induced neuroprotective changes in inhibitory/excitatory pathway expression. The in vitro study informed the compounds utilised in a guinea pig model of c-section preterm birth, which demonstrated impairments consistent within the induced preterm delivery study. Neurosteroid replacement using tiagabine and zuranolone were found to protect against preterm associated impairments in a sexually dimorphic manner, with both treatments demonstrating benefits in both sexes. In conclusion, this project provides new insights into the mechanistic impacts of preterm birth upon the cerebellum and identified the potential for sex specific neurosteroid therapies which protect against the development of neurobehavioral pathology and therefore provide long-term benefit for preterm born individuals.