# Novel Roles of Placental Allopregnanolone in Brain Development and Injury

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $333,396

## Abstract

ABSTRACT
Compromised placental function is highly associated with abnormal fetal development, especially of the brain.
Abnormal brain development or fetal brain injury leads to life-long neurological impairments, including cerebral palsy,
seizures and mental disabilities. Placental dysfunction may place many thousands of fetuses at risk of life-long
impairments each year. The vast majority of research connecting placental compromise to fetal brain injury
has focused on gas exchange or nutritional programming, neglecting the placenta's essential neuroendocrine
role. Using new molecular models, we are testing our overall hypothesis that key placental hormones
contribute to normal brain development and that their loss contributes to injury. One such critical placental
hormone is allopregnanolone (ALLO), the most potent GABAergic neurosteroid derived from progesterone. In
both rodent and human gestation, ALLO is made predominantly by the placenta. Our preliminary experiments
have shown that pharmacological ALLO reduction during gestation disrupts cortico-hippocampal circuit
maturation and alters GABAergic subunit expression. Additionally, endogenous and exogenous ALLO provides
neuroprotection in multiple preclinical injury models. To use ALLO as a perinatal therapeutic agent, however, it
is critical to understand the specific source, physiological levels and actions of ALLO in gestation. Until now,
these investigations have been limited by lack of tools designed to precisely alter and measure placental
neurosteroids, barriers we have overcome through generation of new mouse models and use of advanced
mass spectroscopy. We have generated mouse models in which ALLO production is suppressed only in
placenta. These models allow direct placental steroid manipulation for the first time. We have shown that
suppression of placental ALLO production results in a specific reduction of proliferating intermediate
progenitor cells (IPCs) in the cortical subventricular zone during gestation and that there are long-lasting
functional neurological alterations after placental ALLO is suppressed. Using our new floxed mouse model
(AKR1c14fl/fl) in which the gene for 3αHSD can be deleted in a tissue-specific manner, we will determine the
extent to which placental ALLO is critical to: 1) corticogenesis; 2) long-term behavior and circuit function;
and 3) injury that may be amenable to perinatal treatment. Elucidation of the mechanisms by which
placental hormones, including ALLO, shape normal and abnormal cortical development would
fundamentally change our understanding of developmental brain disorders and the placenta's role in shaping
long-term neurological outcomes. These experiments also provide the possibility to prevent or ameliorate
developmental brain injury through novel therapies based on placental hormones.

## Key facts

- **NIH application ID:** 10213791
- **Project number:** 5R01HD092593-05
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** ANNA A PENN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $333,396
- **Award type:** 5
- **Project period:** 2020-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10213791

## Citation

> US National Institutes of Health, RePORTER application 10213791, Novel Roles of Placental Allopregnanolone in Brain Development and Injury (5R01HD092593-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10213791. Licensed CC0.

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