Comparative study of the effects of prenatal sevoflurane exposure at different cortical stages on forebrain development and maturation in offspring

Tianyuan Wang ¹ Huandi Weng ² Yalan Li ^3*

• ¹ Ningxia Medical University, Yinchuan, Ningxia, China
• ² Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, China
• ³ First Affiliated Hospital of Jinan University, Guangzhou, China

Brain development involves several critical stages, including proliferation, neuronal migration, axonal pathfinding, and connection formation. As a γ-aminobutyric acid (GABA) receptor agonist, sevoflurane is widely used as an inhaled general anaesthetic, and its effect on brain development has gradually become a concern. Here, we compared the effects of prenatal sevoflurane exposure (PSE) at different cortical stages, including embryonic days (E) 12.5 and 18.5. Double in situ hybridization revealed that GABA receptors were coexpressed in Pax6-and Mash1-positive cells in the forebrain. PSE inhibits progenitor cell proliferation and migration and promotes GABAergic neuron tangential migration. Exposure at different cortical stages results in different types of toxicity to glutamatergic neurons. Specifically, early exposure (E12.5) inhibited the expression of the Pax6-Tbr2-Tbr1 cascade and the radial migration of Tbr1 in the ventral prefrontal cortex (PFC), whereas late exposure (E18.5) inhibited this process on the dorsal side. In addition, offspring mice with PSE exhibited increased anxiety-like behaviors, rather than depression, as demonstrated by reduced time spent in the center of the open-field test and in the open arms of the elevated plus-maze test, with no significant differences observed in the forced swim test, tail suspension test, and sucrose preference test, as well as learning and memory impairments in the Morris water maze. Our results indicate that PSE at E12.5 and E18.5 leads to abnormalities in progenitor cell proliferation and migration, affecting long-term anxiety-like behaviours and causing learning and memory impairments in offspring mice.