Compromised placental function or premature loss has been linked to diverse neurodevelopmental disorders. Here we show that placenta allopregnanolone (ALLO), a progesterone-derived GABA-A receptor (GABAAR) modulator, reduction alters neurodevelopment in a sex-linked manner. A new conditional mouse model, in which the gene encoding ALLO’s synthetic enzyme (akr1c14) is specifically deleted in trophoblasts, directly demonstrated that placental ALLO insufficiency led to cerebellar white matter abnormalities that correlated with autistic-like behavior only in male offspring. A single injection of ALLO or muscimol, a GABAAR agonist, during late gestation abolished these alterations. Comparison of male and female human preterm infant cerebellum also showed sex-linked myelination marker alteration, suggesting similarities between mouse placental ALLO insufficiency and human preterm brain development. This study reveals a new role for a placental hormone in shaping brain regions and behaviors in a sex-linked manner. Placental hormone replacement might offer novel therapeutic opportunities to prevent later neurobehavioral disorders.

Prematurity is associated with significantly increased risk of neurobehavioral pathologies, including autism and schizophrenia. A common feature of these psychiatric disorders is prefrontal cortex (PFC) inhibitory circuit disruption due to GABAergic interneuron alteration. Cortical interneurons are generated and migrate throughout late gestation and early infancy, making them highly susceptible to perinatal insults such as preterm birth. Term and preterm PFC pathology specimens were assessed using immunohistochemical markers for interneurons. Based on the changes seen, a new preterm encephalopathy mouse model was developed to produce similar PFC interneuron loss. Maternal immune activation (MIA; modeling chorioamnionitis, associated with 85% of extremely preterm births) was combined with chronic sublethal hypoxia (CSH; modeling preterm respiratory failure), with offspring of both sexes assessed anatomically, molecularly and neurobehaviorally. In the PFC examined from the human preterm samples compared to matched term samples at corrected age, a decrease in somatostatin (SST) and calbindin (CLB) interneurons was seen in upper cortical layers. This pattern of interneuron loss in upper cortical layers was mimicked in the mouse PFC following the combination of MIA and CSH, but not after either insult alone. This persistent interneuron loss is associated with postnatal microglial activation that occurs during CSH only after MIA. The combined insults lead to long-term neurobehavioral deficits which parallel human psychopathologies that may be seen after extremely preterm birth. This new preclinical model supports a paradigm in which specific cellular alterations seen in preterm encephalopathy can be linked with a risk of neuropsychiatric sequela. Specific interneuron subtypes may provide therapeutic targets to prevent or ameliorate these neurodevelopmental risks.

Importance Preeclampsia and depression are two most prevalent disorders known to affect pregnant women and unborn infant. However, few studies have prospectively examined the adverse influence of the in-utero exposures to the two disorders on the optimal development in their offspring, including mortality, adverse birth outcomes, and infant temperament styles. Objectives (1) To examine whether exposures to preeclampsia and antenatal depression were associated with developmental indices of offspring at birth and temperament at 3 months; and (2) To evaluate how preeclampsia and antenatal depression associated with offspring temperamental style. Design Prospective cohort study with regular assessment of mother’s blood pressure at each prenatal visit: offspring were followed till 3 months. Setting Two prenatal clinics, New York City, USA. Participants A cohort of 233 pregnant women was followed throughout pregnancy. Of those, 141 provided ratings of infant temperament at three months. Exposures Diagnostic outcome of maternal depression by clinical interviewers blind to preeclampsia status, were ascertained using the Structured Clinical Interview for DSM-IV Axis I Disorders. The development of preeclampsia, defined by the onset of hypertension (> 140/90 mm HG) after 20 weeks’ gestation, accompanied by 300 mg of protein, monitored via electronic medical records. Main Outcome Measures Birth outcomes were assessed via standardized ratings at delivery. Infant temperament was reported by the mother at three months, using 91-item IBQ-R (Infant Behavioral Questionnaire-Revised). Results Preeclampsia was associated with an over 5-fold increased risk for fetal/infant mortality, a 3- to 7-fold increased risk for poorer birth outcomes, and flatter affect and distress in infants. Furthermore, infants born to preeclamptic mothers with co-occurring depression displayed lower levels of smile/laughter, high-intensity pleasure seeking behavior, perceptual sensitivity, and approach behavior. Conclusion Preeclampsia was associated with a few difficult temperament styles in the first three months after birth. Moreover, its negative impact was amplified by mother’s antenatal depression. Our findings regarding additive risk for negative infant outcomes in babies exposed to preeclampsia and antenatal depression suggests that the development of early detection programs to identify and monitor women who are at heightened risk for these conditions can potentially have a positive influence on long-term infant neurobehavioral development.

Placental endocrine function is essential to fetal brain development. Placental hormones include neurosteroids such as allopregnanolone (ALLO), a regulator of neurodevelopmental processes via positive allosteric modulation of the GABAA receptor (GABAA-R). Using a mouse model (plKO) in which the gene encoding the ALLO synthesis enzyme is specifically deleted in trophoblasts, we previously showed that placental ALLO insufficiency alters cerebellar white matter development and leads to male-specific autistic-like behavior. We now demonstrate that the lack of placental ALLO causes female-predominant alterations of cortical development and function. Placental ALLO insufficiency disrupts cell proliferation in the primary somatosensory cortex (S1) in a sex-linked manner. Early changes are seen in plKO embryos of both sexes, but persist primarily in female offspring after birth. Adolescent plKO females show significant reduction in pyramidal neuron density, as well as somatosensory behavioral deficits as compared with plKO males and control littermates. Assessment of layer-specific markers in human postmortem cortices suggests that preterm infants may also have female-biased abnormalities in cortical layer specification as compared with term infants. This study establishes a novel and fundamental link between placental function and sex-linked long-term neurological outcomes, emphasizing the importance of the growing field of neuroplacentology.