CircPDS5B knockdown attenuates sevoflurane-induced developmental neurotoxicity and associated intracellular alkalinization.

Neonatal sevoflurane exposure can cause developmental neurotoxicity, but the molecular events linking anesthetic exposure to neuronal injury remain incompletely understood. We examined whether circPDS5B-associated disruption of intracellular acid-base homeostasis contributes to this injury. Primary hippocampal neurons and postnatal day 5 (P5) rats were exposed to 4.0% sevoflurane for 6 h. Cultured neurons were transduced with adenovirus on day 4 in vitro (DIV 4), and neonatal rats received bilateral microinjections of Ad-sh-circPDS5B into hippocampal CA1 at P3. In vitro, sevoflurane increased circPDS5B expression, reduced miR-92a-3p and carbonic anhydrase IX (CA9) levels, and induced intracellular alkalinization, reduced viability, and organelle ultrastructural abnormalities. Dual-luciferase assays supported a sequence-specific interaction between circPDS5B and miR-92a-3p. CircPDS5B knockdown increased miR-92a-3p and CA9 expression toward control levels, attenuated intracellular alkalinization, and was associated with less prominent mitochondrial and endoplasmic reticulum ultrastructural abnormalities. In vivo, circPDS5B knockdown attenuated the sevoflurane-associated reductions in hippocampal CA9 expression and CA1 dendritic spine density and was associated with improved subsequent behavioral performance in the Morris water maze and open-field test. These findings support an association between circPDS5B dysregulation, altered intracellular pH regulation, and sevoflurane-induced developmental neurotoxicity. The circPDS5B/miR-92a-3p/CA9 axis should be considered a candidate regulatory mechanism pending pathway-specific rescue experiments.