Calcium Signaling Dysregulation as a Convergent Mechanism in Anesthetic-Induced Developmental Neurotoxicity

Exposure to general anesthetics during critical periods of brain development is associated with altered neurogenesis and long-term neurobehavioral abnormalities in preclinical models, although clinical evidence remains inconclusive. Dysregulation of intracellular calcium signaling has emerged as an important convergent mechanism underlying anesthetic-induced developmental neurotoxicity (AIDN). Calcium serves as a pivotal second messenger regulating neural stem cell (NSC) quiescence, proliferation, fate specification, neuronal maturation; its precise spatiotemporal dynamics are essential for normal brain development. Common anesthetics including propofol, ketamine, sevoflurane, isoflurane, and midazolam act primarily as GABA_A receptor agonists and/or NMDA receptor antagonists, thereby disrupting calcium homeostasis by altering calcium influx, increasing intracellular release from the endoplasmic reticulum and mitochondria, or disrupting calcium oscillations. These alterations involve key molecular pathways, including inositol-1,4,5-trisphosphate receptors (InsP₃Rs) and ryanodine receptors (RyR) mediated calcium release, mitochondrial calcium overload, and activation of calcium-dependent signaling cascades such as CaMK, CREB, and calcineurin/NFAT pathways. Sustained cytosolic calcium elevation triggers mitochondrial dysfunction, oxidative stress, apoptosis, autophagy, and neurogenesis. This review summarizes evidence linking anesthetic exposure to calcium dysregulation, with an emphasis on neurogenesis and NSC biology. Importantly, it highlights calcium signaling as a potential mechanistic bridge between anesthetic exposure and neurodevelopmental outcomes. Despite substantial preclinical evidence, the translation of these findings to clinical pediatric anesthesia remains limited, underscoring a critical knowledge gap. A better understanding of calcium-dependent mechanisms may inform the development of targeted neuroprotective strategies and improve the safety of anesthetic exposure during early life.