Selegiline prevents cognitive impairment and hippocampal CA1 excitability deficits induced by repeated isoflurane exposure

Postoperative cognitive dysfunction (POCD) is a common and clinically significant complication following anesthesia and surgery, affecting up to 40% of elderly patients, yet no established preventive therapy is currently available. Although neuroinflammation has been widely implicated in POCD, the electrophysiological mechanism linking anesthetic exposure to cognitive decline remains poorly understood, and pharmacological approaches to prevent this pathological cascade have not been established. To isolate the contribution of repeated anesthesia exposure itself, independent of surgical trauma, we used a repeated isoflurane-exposure mouse model, which we refer to as anesthesia-induced cognitive impairment (AICI). Using this model, we show that repeated anesthesia produces significant impairments in spatial working memory and recognition memory, accompanied by impaired hippocampal CA1 long-term potentiation (LTP). Whole-cell patch-clamp recordings further revealed intrinsic hypoexcitability of CA1 pyramidal neurons in isoflurane-exposed mice, characterized by reduced firing frequency, prolonged action potential half-width, slower repolarization, and diminished afterhyperpolarization. Reduced spontaneous excitatory postsynaptic current (sEPSC) frequency and amplitude further indicated impaired excitatory synaptic drive in CA1 neurons. Notably, pretreatment with selegiline, an FDA-approved selective monoamine oxidase-B (MAO-B) inhibitor, prevented isoflurane-induced cognitive deficits, preserved hippocampal LTP, preserved intrinsic neuronal excitability, and largely normalized action potential kinetics while maintaining sEPSC frequency, although the reduction in sEPSC amplitude was not significantly prevented by pretreatment. In contrast, direct application of high-concentration selegiline impaired LTP induction. Together, these findings identify impaired CA1 neuronal excitability and excitatory synaptic drive as key electrophysiological correlates of AICI and suggest selegiline as a promising pre-emptive candidate for mitigating anesthesia-related cognitive decline.