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

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.