Role of GABAA receptor depolarization-mediated VGCC activation in sevoflurane-induced cognitive impairment in neonatal mice
Shuang Zeng, Ruilou Zhu, Yangyang Wang, Yi Yang, Ningning Li, Ningning Fu, Mingyang Sun, Jiaqiang Zhang
Abstract
Background In neonatal mice, anesthesia with sevoflurane depolarizes the GABA Type A receptor (GABA A R), which leads to cognitive impairment. Calcium accumulation in neurons can lead to neurotoxicity. Voltage-gated calcium channels (VGCCs) can increase intracellular calcium concentration under isoflurane and hypoxic conditions. The underlying mechanisms remain largely unknown. Methods Six-day-old mice were anesthetized with 3% sevoflurane for 2 h/day for 3 days. The Y-Maze, new object recognition (NOR) test, the Barnes maze test, immunoassay, immunoblotting, the TUNEL test, and Golgi–Cox staining were used to assess cognition, calcium concentration, inflammatory response, GABA A R activation, VGCC expression, apoptosis, and proliferation of hippocampal nerve cells in mice and HT22 cells. Results Compared with the control group, mice in the sevoflurane group had impaired cognitive function. In the sevoflurane group, the expression of Gabrb3 and Cav1.2 in the hippocampal neurons increased ( p < 0.01), the concentration of calcium ions increased ( p < 0.01), inflammatory reaction and apoptosis of neurons increased ( p < 0.01), the proliferation of neurons in the DG area decreased ( p < 0.01), and dendritic spine density decreased ( p < 0.05). However, the inhibition of Gabrb3 and Cav1.2 alleviated cognitive impairment and reduced neurotoxicity. Conclusions Sevoflurane activates VGCCs by inducing GABA A R depolarization, resulting in cognitive impairment. Activated VGCCs cause an increase in intracellular calcium concentration and an inflammatory response, resulting in neurotoxicity and cognitive impairment.