Neuroligin1 in excitatory synapses contributes to long-term cognitive impairments after repeated neonatal sevoflurane exposures

Currently, millions of pediatric patients require surgery/anesthesia each year in the world (Ing et al., 2012; Servick, 2014). General anesthesia in children has been considered safe and without long-term adverse effects. However, in February 2017, the US Food and Drug Administration (FDA) issued a “Drug Safety Notice” based on research findings, stating that repeated or prolonged use of general anesthesia or sedatives during surgery or medical procedures in infants and young children under the age of 3, or during the third trimester (8–10 months of pregnancy) may affect the child's brain development (Andropoulos and Greene, 2017). Animal experimental results also suggested that anesthetics can trigger neurotoxic effects in young animals, leading to neuronal apoptosis and affecting long-term cognitive function (Makaryus et al., 2015; Makaryus et al., 2018; Zhang et al., 2016). Therefore, intensive research on the mechanism of neurotoxicity of general anesthetics in animal experiments will provide a reference for the selection of appropriate general anesthetics and methods during surgery in infants and young children. The study of its mechanism is crucial for us to have a clearer understanding of the role of sevoflurane in affecting learning and memory function, and has significant social and practical significance.

The normal synaptic structure and function are the cellular biological basis for learning and memory (Fuchsberger and Paulsen, 2022; Wemmie et al., 2002). Neuroligin1 (NL1) belongs to the family of cell adhesion molecules (CAMs) and is a type of cell adhesion molecule located in the postsynaptic membrane of neurons that mediates synaptogenesis (Song et al., 1999). An influential animal study demonstrated that NL1 is essential for normal excitatory transmission and long-term synaptic plasticity in the hippocampus of intact animals (Jedlicka et al., 2015). Postsynaptic density protein 95 (PSD95) is a scaffolding protein that regulates the synaptic localization of many receptors, channels, and signaling proteins (Jeong et al., 2019). NL1 binding to PSD95 plays an important role in the formation and function of excitatory synapses, and the interaction between NL1 and PSD95 enhances excitatory synaptic function and glutamate neurotransmitter transmission, disrupting the effective activity of neural networks (Guo et al., 2018). A study has shown that knocking out NL1 can reduce the recruitment of postsynaptic AMPA receptor and NMDA receptor in the hippocampus, reduce excitatory synaptic transmission, and damage long-term potentiation to the hippocampus (Jedlicka et al., 2015). Previous study has shown that the upregulation of NL1 contributed to neuropathic pain (Ouyang et al., 2021). There are also studies indicating that surgery decreased NL1, which contributed to the development of postoperative cognitive dysfunction (POCD)(Min et al., 2022). The reduction of NL1 leads to synaptic and memory deficits in Alzheimer's disease, which has also been reported (Arias-Aragón et al., 2023). However, it is currently unclear whether abnormalities in excitatory synaptic transmission mediated by the NL1/PSD95 interaction are involved in the development of cognitive impairment caused by repeated exposures to sevoflurane.

Synaptic transmission plays a crucial role in maintaining a balance between excitatory and inhibitory synapses (Noh et al., 2023; Yang et al., 2014). The excitation/inhibition (E/I) balance controls the synaptic inputs to prevent the inappropriate responses of neurons to input strength and is required to restore the initial pattern of network activity (Lopatina et al., 2019). The vesicular GABA transporter (vGAT), also known as vesicular inhibitory amino acid transporter (VIAAT), is a common vesicle transporter for GABA and glycine and is essential for normal GABAergic and glycinergic neurotransmission (Bolneo et al., 2022). vGAT usually labels inhibitory synaptic inputs. The balance between excitatory and inhibitory synapses plays an important role in the expression of sensory information, execution of command signals, and higher cognitive functions, and its imbalance can trigger various neuropsychiatric disorders such as epilepsy, schizophrenia, and Alzheimer's disease (Dejanovic et al., 2022; Gawande et al., 2023; Wang et al., 2021). One study demonstrated that reduced inhibition might contribute to early life LPS exposure induced-cognitive impairment (Wu et al., 2022). Another demonstrated that prenatal sevoflurane exposure causes neuronal excitatory/inhibitory imbalance in the prefrontal cortex and neurofunctional abnormality in rats (Zhao et al., 2020). However, it is unclear whether the sevoflurane-induced cognitive impairment model affects the synaptic excitation/inhibition balance in the hippocampus of neonatal rats.

Thus, we boldly speculated that upregulation or downregulation of NL1 in the hippocampus will affect the transmission of excitatory synapses, disrupt the excitatory signals sent by pyramidal cells to inhibitory interneurons, leading to impaired function of inhibitory interneurons and weakened inhibition of pyramidal cells, resulting in an imbalance of excitatory/inhibitory synaptic transmission in the hippocampus and cognitive dysfunction.

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