Lack of placental neurosteroid alters cortical development and female somatosensory function

Abstract

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.

Characterization of placental endocrine function and fetal brain development in a mouse model of small for gestational age

“…In mice, placental metabolism of serotonin is critical for fetal forebrain development. Others have found that placental allopregnanolone deficiency in mice alters cerebellar white matter development and programmes postnatal autistic-like behaviour in the offspring (24). Therefore, these studies suggest a potential link between placental endocrine function, fetal growth and fetal neurodevelopment, which could have long last effects on neurocognitive health outcomes.…”

“…However, the placenta is also a powerful endocrine organ that secretes an abundance of hormones and growth factors into the maternal and fetal circulation that allow for fetal development and pregnancy maintenance (15-20). Indeed, there is now growing evidence suggesting that placental metabolism and function impact on fetal brain development (21)(22)(23)(24)(25)(26)(27). For example, in mice, there is genomic linkage between placental and the fetal hypothalamic development (28).…”

Constitutive and conditional deletion reveals distinct phenotypes driven by developmental versus neurotransmitter actions of the neuropeptide PACAP

“…PACAP is produced in both the maternal and fetal compartments and crosses the blood brain barrier 67,68 . Placental factors are often involved in neurodevelopment 69–72 . Our constitutive PACAPko mice are generally bred homozygously, such that neither the fetal nor maternal placental compartments produce PACAP.…”

“…67,68 Placental factors are often involved in neurodevelopment. [69][70][71][72] Our constitutive PACAPko mice are generally bred homozygously, such that neither the fetal nor maternal placental compartments produce PACAP. Here, we used dams heterozygous for PACAP crossed with homozygous PACAPko sires to test the effects of placental PACAP in our animals.…”

Impact of maternal immune activation and sex on placental and fetal brain cytokine and gene expression profiles in a preclinical model of neurodevelopmental disorders

“…Others have found that gestational MIA alters the switch between excitatory and inhibitory signaling in offspring, potentially driven by IL-1R1 activity [ 16 ]. Altered placental production of allopregnanolone in females, a hormone that regulates gamma-aminobutyric acid receptors and therefore the excitatory/inhibitory balance, also contributes to altered behavior [ 6 ]. Therefore, it is possible that gestational MIA results in a female specific effect on the placental programs involved in the excitatory and inhibitory systems.…”