# Prenatal alcohol exposure perturbs the development of radial glial cells in the fetal olfactory bulb

## TL;DR

Prenatal alcohol exposure disrupts the development of brain cells in the fetal olfactory bulb, leading to delays in cell division and potential olfactory dysfunction.

## Contribution

This study identifies GABA(A) receptor-mediated mTOR signaling as a novel mechanism linking prenatal alcohol exposure to olfactory dysfunction.

## Key findings

- Prenatal alcohol exposure causes G2/M arrest in radial glial cells of the olfactory bulb, delaying neurogenesis.
- GABA(A) receptor-mediated mTOR signaling downregulation contributes to the effects of prenatal alcohol exposure on radial glial cells.
- Impaired radial glial cell migration and differentiation may underlie olfactory dysfunction in fetal alcohol spectrum disorder.

## Abstract

Prenatal alcohol exposure (PAE) causes fetal alcohol spectrum disorder (FASD) and is associated with various cognitive and sensory impairments, including olfactory dysfunction. While both genetic and environmental factors contribute to olfactory dysfunction, PAE is considered a significant factor affecting brain development, including the olfactory system. In this study, we investigated the impact of PAE on the developing olfactory bulb (OB), specifically focusing on OB RGCs—radial glial cells that give rise to OB projection neurons.

Ethanol was administered to pregnant mice at embryonic day (E) 11, a time point when OB RGCs generate the highest number of mitral cells—a major class of OB projection neurons. To investigate the impact of PAE on OB RGCs, BrdU was injected 30 min prior to ethanol administration to label OB RGCs in the S phase of the cell cycle. The location and differentiation of BrdU+ cells were subsequently examined in the developing OB at E11, E13, and E15. We also assessed whether inhibition of GABA(A) receptors could mitigate the effects induced by PAE.

PAE was found to impair the progression of migration of OB RGC nuclei to the apical side of the ventricular zone for mitosis, indicating the inhibition of the transition from the S phase to the M phase (G2/M arrest). Therefore, PAE delays neurogenesis of OB RGCs. Importantly, our findings suggest that GABAergic signaling mediated by the mTOR signaling plays a critical role in these PAE‐induced effects.

These findings provide insights into the mechanisms by which PAE disrupts OB development by impairing neurogenesis of RGC, contributing to a better understanding of the underlying mechanisms of olfactory dysfunction observed in FASD.

Prenatal alcohol exposure affects the development of radial glial cells (RGCs) in the embryonic mouse olfactory bulb. Ethanol administered at embryonic day 11, a time point when RGCs generate the largest number of mitral cells, caused G2/M arrest in RGCs, delaying their progression to mitosis and subsequent neuronal differentiation. This study also found that GABA(A) receptor‐mediated mTOR signaling downregulation contributes to these effects. These findings highlight a potential mechanism underlying the olfactory dysfunction observed in fetal alcohol spectrum disorder.