Background Postoperative cognitive dysfunction (POCD) is a common complication following anesthesia and surgery. General anesthetic isoflurane has potential neurotoxicity and induces cognitive impairments, but the exact mechanism remains unclear. Astrocytes form interconnected networks in the adult brain through gap junctions (GJs), which primarily comprise connexin 43 (Cx43), and play important roles in brain homeostasis and functions such as memory. However, the role of the GJ-Cx43-mediated astrocytic network in isoflurane-induced cognitive dysfunction has not been defined. Methods 4-month-old male C57BL/6 mice were exposure to long-term isoflurane to induce cognitive impairment. To simulate an in vitro isoflurane-induced cognitive dysfunction‐like condition, primary mouse astrocytes were subjected to long-term isoflurane exposure. Cognitive function was assessed by Y-maze and fear conditioning tests. Western blot was used to determine the expression levels of different functional configurations of Cx43. The morphology of the GJs-Cx43 was evaluated by immunofluorescence staining. Levels of IL-1β and IL-6 were examined by ELISA. The ability of GJs-Cx43-mediated intercellular communication was examined by lucifer yellow dye transfer assay. Ethidium bromide uptake assays were used to measure the activity of Cx43 hemichannels. The ultrastructural morphology of astrocyte gap junctions and tripartite synapse were observed by transmission electron microscopy. Results After long-term isoflurane anesthesia, the GJs formed by Cx43 in the mouse hippocampus and primary mouse astrocytes were significantly reduced, GJs function was impaired, hemichannel activity was enhanced, the levels of IL-1β and IL-6 were increased, and mice showed significant cognitive impairment. After treatment with the novel GJ-Cx43 enhancer ZP1609, GJ-Cx43-mediated astrocytic network function was enhanced, neuroinflammation was alleviated, and ameliorated cognition dysfunction induced by long-term isoflurane exposure. However, ZP1609 enhances the astrocytic network by promoting Cx43 to form GJs without affecting hemichannel activity. Additionally, our data showed that long-term isoflurane exposure does not alter the structure of tripartite synapse. Conclusion Our results reveal a novel mechanism of the GJ-Cx43-mediated astrocytic network involved in isoflurane-induced neuroinflammation and cognitive impairments, which provides new mechanistic insight into the pathogenesis of POCD and identifies potential targets for its treatment.
Aim Astrocytes are connected by gap junctions Connexin43 (GJs‐Cx43) forming an extensive intercellular network and maintain brain homeostasis. Perioperative neurocognitive disorder (PND) occurs frequently after anesthesia/surgery and worsens patient outcome, but the neural circuit mechanisms remain unclear. This study aimed to determine the effects of the GJs‐Cx43–mediated astrocytic network on PND and ascertain the underlying neural circuit mechanism. Methods Male C57BL/6 mice were treated with long‐term isoflurane exposure to construct a mouse model of PND. We also exposed primary mouse astrocytes to long‐term isoflurane exposure to simulate the conditions of in vivo cognitive dysfunction. Behavioral tests were performed using the Y‐maze and fear conditioning (FC) tests. Manganese‐enhanced magnetic resonance imaging (MEMRI) and resting‐state functional magnetic resonance imaging (rs‐fMRI) were used to investigate brain activity and functional connectivity. Western blot and flow cytometry analysis were used to assess protein expression. Results Reconfiguring the astrocytic network by increasing GJs‐Cx43 expression can modulate 22 subregions affected by PND in three ways: reversed activation, reversed inhibition, and intensified activation. The brain functional connectivity analysis further suggests that PND is a brain network disorder that includes sleep‐wake rhythm–related brain regions, contextual and fear memory–related subregions, the hippocampal‐amygdala circuit, the septo‐hippocampal circuit, and the entorhinal‐hippocampal circuit. Notably, remodeling the astrocytic network by upregulation of GJs‐Cx43 can partially reverse the abnormalities in the above circuits. Pathophysiological degeneration in hippocampus is one of the primary hallmarks of PND pathology, and long‐term isoflurane anesthesia contributes to oxidative stress and neuroinflammation in the hippocampus. However, promoting the formation of GJs‐Cx43 ameliorated cognitive dysfunction induced by long‐term isoflurane anesthesia through the attenuation of oxidative stress in hippocampus. Conclusion Enhancing GJs‐Cx43 coupling can improve brain network abnormalities and cognitive impairment induced by long‐term isoflurane anesthesia, its mechanisms might be associated with the regulation of oxidative stress and neuroinflammation.
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