Munc18-1 Contributes to Hippocampal Injury in Septic Rats Through Regulation of Syntanxin1A and Synaptophysin and Glutamate Levels

Abstract

Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction closely associated with mortality in the acute phase of sepsis. Abnormal neurotransmitters release, such as glutamate, plays a crucial role in the pathological mechanism of SAE. Munc18-1 is a key protein regulating neurotransmission. However, whether Munc18-1 plays a role in SAE by regulating glutamate transmission is still unclear. In this study, a septic rat model was established by the cecal ligation and perforation. We found an increase in the content of glutamate in the hippocampus of septic rat, the number of synaptic vesicles in the synaptic active area and the expression of the glutamate receptor NMDAR1. Meanwhile, it was found that the expressions of Munc18-1, Syntaxin1A and Synaptophysin increased, which are involved in neurotransmission. The expression levels of Syntaxin1A and Synaptophysin in hippocampus of septic rats decreased after interference using Munc18-1siRNA. We observed a decrease in the content of glutamate in the hippocampus of septic rats, the number of synaptic vesicles in the synaptic activity area and the expression of NMDAR1. Interestingly, it was also found that the down-regulation of Munc18-1 improved the vital signs of septic rats. This study shows that CLP induced the increased levels of glutamate in rat hippocampus, and Munc18-1 may participate in the process of hippocampal injury in septic rats by affecting the levels of glutamate via regulating Syntaxin1A and Synaptophysin. Munc18-1 may serve as a potential target for SAE therapy.

The role of the peripheral system dysfunction in the pathogenesis of sepsis-associated encephalopathy

“…The abundance of synaptic glutamate can excessively activate NMDAR, thus resulting in excitotoxicity and subsequent harm to nerve cells ( Asada et al, 2022 ). The research has shown that CLP rats exhibit elevated levels of glutamate in the hippocampus, in conjunction with an upregulated expression of the NMDAR1 glutamate receptor ( Tang et al, 2023 ). Syntaxin1A primarily serves as an indicator for synaptic vesicles abundance in synaptically active regions ( Ullrich et al, 2015 ).…”

“…Additionally, the expression levels of Syntaxin1A, synapsin and glutamate decreased after interference with Munc18-1 siRNA. These indicated that Munc18-1 may affect glutamate levels by regulating Syntaxin1A and synapsin, thereby participating in the process of hippocampal injury in septic rats ( Tang et al, 2023 ).…”