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

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.