Pregnancy compromises: role of neurosteroids in neurodevelopment and behaviour

Research Doctorate - Doctor of Philosophy (PhD)Pregnancy compromises impact a number of infants annually around the world. These include intrauterine growth restriction (IUGR), maternal psychological stress (prenatal stress; PS) and preterm birth (PTB). These compromises can result in alterations to the normal neurodevelopmental process in key brain regions, including the hippocampus, cerebellum and amygdala. These changes in fetal development are being increasingly attributed to the programming of fetal systems in utero towards negative <i>ex utero</i> events. In fetal life, IUGR, PS and PTB cause a delay and/or reduction in mature myelin, concurrent with an alteration in astrocyte activation. Infants born following IUGR, PS and PTB are more likely to develop cognitive deficits, anxiety, behaviours disorders and schizophrenia. The progesterone metabolite, allopregnanolone is a key neurosteroid involved in fetal development. Allopregnanolone promotes myelination, inhibits astrocytosis, and has allosteric action at the γ-aminobutyric acid type A (GABA_A) receptor to modulate neural excitability. Allopregnanolone synthesis is upregulated following various acute neurological insults, including hypoxia and stress, protecting against excitotoxic cell death. Inhibition of allopregnanolone synthesis in late gestation, as may occur in chronic pregnancy compromises, reduces myelination and up-regulates astrocyte activation. In later life, dysregulation of allopregnanolone is implicated in several psychological disorders such as depression, and premenstrual dysphoric disorder. Little information exists on the effect of major pregnancy compromises, their contribution to neurosteroid dysfunction, and neurodevelopmental and behavioural outcomes of the offspring. The effect of inhibiting allopregnanolone synthesis, using finasteride, in late gestation on postnatal cerebellar development was investigated in a guinea pig model. At 8 days postnatal age there was increased astrocyte activation and decreased expression of the allopregnanolone-sensitive GABA_AR α6 subunit in the cerebella of neonates exposed to finasteride. This demonstrates the ongoing effects of a low neurosteroid environment in pregnancy extending into childhood. At 21 days postnatal age, females with <i>in utero</i> finasteride exposure displayed increased neophobia-like responses to changes in their environment. This was without ongoing effects on myelin, astrocyte or GABAergic enzyme expression in the hippocampus or amygdala. These observations suggest that prenatal loss of neurosteroids programs an anxious phenotype in females, possibly by inducing deficits in the end-point targets of allopregnanolone action, and does not impact male anxiety development. A model of combined IUGR+PS was used to investigate neurodevelopmental changes of offspring exposed to multiple pregnancy compromises at term. Circulating allopregnanolone and hippocampal myelination in males, whilst reduced in both IUGR and IUGR+PS, was not cumulatively affected by the combination of stressors. Interestingly, the addition of PS to IUGR had a potentially positive effect on subcortical myelination, suggesting the triggering of a protective mechanism, occurring in the fetal neurodevelopment, to preserve an already compromised brain. The placenta contains all the essential enzymes and is the major contributor to fetal allopregnanolone for neurodevelopment Thus the health of the placenta is critical for the development of a healthy fetus. Many preterm infants do not survive the immediate neonatal period, with no overt indicators as to poor health. The placenta of surviving and non-surviving preterm guinea pigs were investigated to determine expression of the allopregnanolone synthesis enzymes. The expression of 5-reductase type 2 was greatest in placentae from neonates that did not survive to 24 hours. This may indicate an upregulation of protective actions to increase allopregnanolone exposure, suggesting these neonates experienced an adverse <i>in utero</i> environment and were therefore more vulnerable to the insult of premature birth. The current body of work indicates that fetal allopregnanolone plays a role in programming GABA_A receptor subunit expression as well as juvenile female behaviour, and thus impaired supply of this steroid <i>in utero</i> may be a predisposing factor in the development of depression and anxiety. Allopregnanolone is implicated in the poor development of myelination following IUGR, yet PS may have a neuroprotective action on myelin development in IUGR male brains. Based on this work, it is also postulated that placental expression of neurosteroid producing enzymes provide identification of neonates at risk of poor outcomes in the immediate neonatal period. Further studies investigating the protective effects of PS in IUGR, and their impacts on later behavioural development are warranted. Future work should investigate the potential of perinatal neurosteroid replacement for the improvement of mental health outcomes following pregnancy compromises