Interaction between transient receptor potential vanilloid 4 and glutamate NMDA receptor subunit 1 mediates endoplasmic reticulum stress and neuroinflammation in postoperative delirium

TL;DR

This study identifies a new pathway involving TRPV4 and GluN1 that causes brain stress and inflammation linked to postoperative delirium, offering a potential treatment target.

Contribution

The study reveals a novel TRPV4-GluN1 interaction that mediates ER stress and neuroinflammation in postoperative delirium.

Findings

TRPV4 interacts with GluN1, enhancing NMDAR signaling and causing ER stress and neuroinflammation.

Pharmacological inhibition of TRPV4 or NMDAR reversed cognitive-affective deficits in a murine model of POD.

TRPV4 was upregulated in early-onset Alzheimer’s disease patients, suggesting broader relevance.

Abstract

Postoperative delirium (POD) is a serious and prevalent neurocognitive complication that poses a major clinical challenge because its mechanism is unclear. This study identifies a pathogenic pathway centred on the direct interaction between transient receptor potential vanilloid 4 (TRPV4) and the essential N-methyl-D-aspartate receptor (NMDAR) subunit GluN1. Using a murine POD model, the neuron-centric glutamatergic dysfunction in the hippocampus was initially confirmed through ex vivo metabolic kinetic analysis. Transcriptomic analysis revealed upregulation of Trpv4, predominantly in neurons. Co-immunoprecipitation coupled with mass spectrometry revealed that TRPV4 directly interacts with GluN1. This enhanced TRPV4-GluN1 coupling promoted GluN1 phosphorylation at serine 896 and hyperactivated NMDAR signalling. We subsequently observed the concurrent induction of endoplasmic reticulum (ER) stress, as evidenced by a dilated ER ultrastructure and the upregulation of the expression of UPR markers (ATF6, p-PERK, p-IRE1α, and CHOP), as well as neuroinflammation, characterized by microglial activation and elevated expression of proinflammatory mediators (IL-6, IL-1β, and ICAM-1). These molecular pathologies were associated with decreased neuronal activity and the characteristic cognitive-affective deficits associated with POD. Critically, both pharmacological inhibition of TRPV4 (HC067047) and hippocampal CA3-specific Trpv4 knockdown reversed these pathologies and rescued the behaviour. Inhibiting NMDAR with MK801 recapitulated these therapeutic benefits. Furthermore, TRPV4 was significantly upregulated in early-onset Alzheimer’s disease patients. Our study defines a novel TRPV4-GluN1 axis that drives POD pathogenesis, suggesting that it is a promising therapeutic target.

The online version contains supplementary material available at 10.1186/s43556-026-00421-8.

Figures