# 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.

## Key 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.