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.

BackgroundIschemic preconditioning (IPC) protects the heart from prolonged ischemic insult and reperfusion injury through a poorly understood mechanism. Post‐translational modifications of histone residues can confer rapid and drastic switches in gene expression in response to various stimuli, including ischemia. The aim of this study was to investigate the effect of histone methylation in the response to cardiac ischemic preconditioning.Methods and ResultsWe used cardiac biopsies from mice subjected to IPC to quantify global levels of 3 of the most well‐studied histone methylation marks (H3K9me2, H3K27me3, and H3K4me3) with Western blot and found that H3K9me2 levels were significantly increased in the area at risk compared to remote myocardium. In order to assess which genes were affected by the increase in H3K9me2 levels, we performed ChIP‐Seq and transcriptome profiling using microarray. Two hundred thirty‐seven genes were both transcriptionally repressed and enriched in H3K9me2 in the area at risk of IPC mice. Of these, Mtor (Mechanistic target of rapamycin) was chosen for mechanistic studies. Knockdown of the major H3K9 methyltransferase G9a resulted in a significant decrease in H3K9me2 levels across Mtor, increased Mtor expression, as well as decreased autophagic activity in response to rapamycin and serum starvation.Conclusions IPC confers an increase of H3K9me2 levels throughout the Mtor gene—a master regulator of cellular metabolism and a key player in the cardioprotective effect of IPC—leading to transcriptional repression via the methyltransferase G9a. The results of this study indicate that G9a has an important role in regulating cardiac autophagy and the cardioprotective effect of IPC.

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