Work

Glucosylceramide regulates depression through activating peroxisome proliferator-activated receptor gamma in dorsal striatum

Year: 2025

Type: article

Abstract: Rationale: Depression is a heterogeneous disorder influenced by cell type-specific gene transcription in the brain.Peroxisome proliferator-activated receptor gamma (PPARγ) plays an important role in modulating the pathophysiology of depression.However, the role of PPARγ signaling in modulating depression-responsive neuronal ensembles remains largely unknown.Methods: We established a chronic restraint stress mouse model and integrated multi-omics and functional approaches to investigate the role of glucosylceramide (GlcCer)-PPARγ signaling in stress-induced depression.Conditional knockout mice targeting glucosylceramide synthase (GCS) or Pparg in dopamine D2 receptor-expressing medium spiny neurons (D2-MSNs) were generated using a Cre-loxP system, and molecular assays were used to characterize GlcCer as an endogenous activator of PPARγ-driven transcriptional programs.Results: GlcCer as a crucial native activator of PPARγ that specifically modulates depression by binding to the activation function 1 domain of PPARγ in D2-MSNs in the dorsal striatum.Genetic ablation of GCS in D2-MSNs disrupts PPARγ signaling and neuronal function, leading to depression-like behaviors in mice.Selective deletion of Pparg in D2-MSNs produces a similar effect through dopamine D2 receptor.Administration of GlcCer or the PPARγ agonist pioglitazone reverses stress-induced depression-like behaviors, combined GlcCer and pioglitazone exerts additive antidepressant effects.Conclusions: These findings demonstrate a pivotal role for GlcCer-PPARγ signaling in D2-MSNs in depression, highlighting the therapeutic potential of targeting PPARγ activity in depression.

Source: Theranostics

DOI: 10.7150/thno.123178