Neonatal sevoflurane exposures induced cognitive impairment via Satb2-mediated synaptic deficits

Background Special AT-rich sequence-binding protein 2 (Satb2) is a DNA binding protein, and involved in transcription regulation and chromatin remodeling. Studies demonstrated that the absence of Satb2 mediated cognitive impairments in humans and rodents. Moreover, animal research reported that neonatal exposure to sevoflurane induced cognitive dysfunction in adolescent period, along with damage of synaptic plasticity, but the mechanisms are still not clear. Herein, we aimed to determine the role of Satb2 in neurotoxicity caused by sevoflurane. Methods A total of 254 neonatal male Sprague-Dawley rats were used in this study. Neonatal rats were exposed to 30% O 2 or 3.0% sevoflurane delivered in 30% O 2 for 3 h on postnatal day 7 (P7). Cognitive function was evaluated through open field, Y maze, and novel object recognition tests from P28 to P35. The hippocampi were harvested on P14, P21, and P35. Effects of sevoflurane on Satb2, and synapse in the hippocampus were investigated by western blot, quantitative real-time polymerase chain reaction (qRT-PCR), and Golgi staining. To further screen key molecules, another batch of hippocampi were harvested immediately and 24 h after gas exposure, and subjected to RNA sequencing. Finally, Satb2 overexpression was induced by lentivirus injection into the lateral ventricle on P1, followed by gas exposure on P7. Next, some rats underwent behavioral tests on P28-P35. Hippocampi from another group of rats were harvested on P35 for Western blot, qRT-PCR, and Golgi staining. Results Y maze test showed that sevoflurane reduced the spontaneous alternation ratio in young rats. Novel object recognition test also revealed that sevoflurane decreased recognition index, the entries, and duration in novel arm, along with prolonged the latency to novel arm. Persistent decrease in Satb2, postsynaptic density protein-95 (PSD95), and spine density were observed. Moreover, RNA sequencing also revealed the decrease in Satb2 mRNA caused by neonatal exposure to sevoflurane. Furthermore, we found that lentivirus (LV)-induced Satb2 overexpression partially restored the decreases in the PSD95, spine density, spontaneous alternation ratio, recognition index, the entries, and duration in novel arm, and the increase in latency to novel arm caused by sevoflurane exposure. Conclusions These results suggest that decreased Satb2 may contribute to cognitive disorders by reducing PSD95 levels, resulting in synaptic deficits. Meanwhile, this emphasizes that Satb2 was a potential target to intervening cognitive impairment caused by sevoflurane exposure.