Integrated ribosome and proteome analysis provides insight into sevoflurane-induced long-term social behavior and cognitive dysfunctions by inhibiting ADNP in neonatal mice

A growing number of studies have identified that repeated exposure to Sevoflurane during development leads to long-term social abnormalities and cognitive impairment. Davunetide is an activity fragment of activity dependent neuroprotective protein (ADNP), which was coupled to social and cognitive protection. Whether Davunetide could attenuate the social deficits after sevoflurane exposure and the underlying developmental mechanisms are poorly understood. In this study, ribosome and proteome profiles were conducted to investigate the molecular basis in neonatal mice with sevoflurane-induced social deficits. We investigated the neuropathological basis through techniques such as Golgi staining, morphological analysis, Western blot, electrophysiology technology, and behavior analysis. Results showed that ADNP was significantly downregulated after Sevoflurane exposure during development. After adulthood, neurons in ACC of sevoflurane exhibited decrease in number of dendrites, total dendrite length and spine density. The expression of Homer, PSD95, synaptophsin and vglut2 were significantly reduced in sevoflurane group. Patch-clamp recording showed that frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) were reduced. Importantly, davunetide significantly alleviated Sevoflurane induced synaptic defect, social behavior and cognitive impairment. Mechanistic analysis revealed that loss of ADNP caused Ca2+ activity dysregulation via Wnt/β-catenin signaling, leading to decreased the expression of synaptic proteins. Wnt suppression was all restored in davunetide-treated group. Taken together, we identified ADNP as a promising therapeutic target for the prevention and treatment of neurodevelopmental toxicity caused by general anesthetics. Our data provide an insight into the social abnormalities and cognitive damage induced by sevoflurane exposure in neonatal mice and its underlying regulatory mechanism.