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Postoperative Impairment of GluA2 Ttrafficking in CA3 Induces Memory Consolidation Deficits in Aged Mice by Disrupting SPW-R in CA1
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DOI：10.1007/s12031-026-02565-2.png)
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Abstract
En 中文
Postoperative cognitive dysfunction (POCD) is a common complication of surgery in elderly patients and is characterized primarily by memory impairment; however, the underlying mechanisms remain incompletely understood. By utilizing a laparotomy model in aged mice and the delayed spatial alternation task (DSAT), we found that surgery specifically impaired the memory consolidation process. Importantly, this impairment was accompanied by significant disruption of sharp-wave ripples (SPW-R) in the hippocampal CA1 region. Previous research has indicated that trafficking of GluA2-containing AMPARs at CA3 recurrent synapses is crucial for SPW-R generation. Therefore, we examined postsynaptic AMPARs in the CA3 region after surgery and observed reduced membrane expression of GluA2-containing AMPARs, although the total protein levels and gene transcription remained unchanged. Immunofluorescence and coimmunoprecipitation revealed significantly decreased colocalization and binding of GluA2 with postsynaptic density protein 95 (PSD95), suggesting impaired synaptic GluA2 trafficking. Importantly, immediate postoperative injection of TAT-GluA23Y into the CA3 region to increase GluA2 synaptic expression significantly ameliorated surgery-induced SPW-R disruption and memory consolidation deficits. Conversely, local injection of a GluA2 cross-linking agent into the CA3 region of aged mice to inhibit GluA2 trafficking mimicked the postoperative phenotypes of SPW-R disruption and memory consolidation deficits. These results reveal that surgical trauma induces impaired GluA2 trafficking at hippocampal CA3, leading to CA1 SPW-R disruption and ultimately resulting in memory consolidation deficits. This discovery provides not only a novel molecular and neural circuit explanation for the pathogenesis of POCD but also an experimental foundation for the development of neuroprotective strategies targeting GluA2 trafficking.
Keywords:
Postoperative cognitive dysfunction (POCD)
Memory consolidation
Sharp-wave ripples (SPW-R)
GluA2 Trafficking
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