TAT-GluA23Y injection reverses postoperative GluA2 trafficking deficits and memory impairment in aged mice

Postoperative cognitive dysfunction (POCD) is a prevalent and debilitating complication in elderly surgical patients, primarily characterized by memory impairment. The precise molecular and neural circuit mechanisms underlying POCD remain largely elusive, hindering the development of effective preventive or therapeutic strategies. Previous research highlights the critical role of AMPARs, particularly GluA2-containing AMPARs, and sharp-wave ripples (SPW-R) in hippocampal CA1 for memory consolidation. This study investigates whether impaired GluA2 trafficking at CA3 recurrent synapses contributes to POCD pathogenesis.

Researchers utilized a laparotomy model in aged mice to induce POCD, assessing memory consolidation using the delayed spatial alternation task (DSAT). They examined postsynaptic AMPARs in the CA3 region, specifically focusing on membrane expression of GluA2-containing AMPARs, total protein levels, and gene transcription. Immunofluorescence and coimmunoprecipitation were used to evaluate GluA2 colocalization and binding with postsynaptic density protein 95 (PSD95). To modulate GluA2 synaptic expression, mice received immediate postoperative local injections of TAT-GluA23Y into the CA3 region. A GluA2 cross-linking agent was also injected into CA3 to inhibit GluA2 trafficking, serving as a control to mimic postoperative phenotypes.

Surgery in aged mice specifically impaired memory consolidation, accompanied by significant disruption of sharp-wave ripples (SPW-R) in the hippocampal CA1 region. Postoperative analysis of the CA3 region revealed reduced membrane expression of GluA2-containing AMPARs, despite unchanged total protein levels and gene transcription. Immunofluorescence and coimmunoprecipitation further demonstrated significantly decreased colocalization and binding of GluA2 with PSD95, indicating impaired synaptic GluA2 trafficking. This impairment directly correlated with SPW-R disruption and memory deficits. Importantly, immediate postoperative injection of TAT-GluA23Y into the CA3 region to enhance 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, designed to inhibit GluA2 trafficking, successfully mimicked the postoperative phenotypes of SPW-R disruption and memory consolidation deficits. This provides strong evidence for the causal role of GluA2 trafficking in POCD.

Immediate postoperative CA3 injection of TAT-GluA23Y significantly ameliorated surgery-induced SPW-R disruption and memory consolidation deficits.