Excitation-inhibition imbalance underlies perioperative neurocognitive disorders: a single-nucleus transcriptomic perspective in mice hippocampus.
Summary
Single-nucleus RNA-seq of 119,109 hippocampal cells from aged mouse PND models revealed excitation–inhibition imbalance with impaired inhibitory control of excitatory plasticity. Distinct astrocyte and oligodendrocyte states linked to E/I imbalance were identified, suggesting multicellular contributions to PND pathogenesis.
Key Findings
- Single-nucleus RNA-seq (119,109 cells) from aged mouse hippocampus shows E/I imbalance with dysregulated inhibitory control of excitatory plasticity in PND.
- Distinct PND-associated astrocyte and oligodendrocyte phenotypes—different from other cognitive disorders—link glial states to E/I imbalance.
- Electrophysiology and protein assays support transcriptomic findings, indicating convergent mechanistic evidence.
Clinical Implications
Motivates perioperative strategies to preserve inhibitory tone and synaptic balance (e.g., choice/dose of anesthetics, analgesics), and development of E/I-targeted therapeutics and biomarkers for cognitive risk stratification.
Why It Matters
Defines a cellular–molecular framework for PND centered on E/I imbalance, guiding biomarker discovery and mechanism-based interventions relevant to anesthesiology.
Limitations
- Mouse-based model without human validation in this study
- Causality for specific cellular targets remains to be established in vivo
Future Directions
Translate signatures to human perioperative cohorts; test interventions restoring E/I balance (e.g., GABAergic modulators) and evaluate anesthetic regimens for cognitive protection.
Study Information
- Study Type
- Basic/Mechanistic research
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical mechanistic evidence from animal models with supportive physiology and protein assays
- Study Design
- OTHER