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

TL;DR

This study shows that glucosylceramide activates PPARγ in specific brain cells to regulate depression, offering new therapeutic possibilities.

Contribution

The study identifies glucosylceramide as a natural activator of PPARγ in D2-MSNs, linking it to depression regulation.

Findings

GlcCer activates PPARγ in D2-MSNs of the dorsal striatum to modulate depression.

Deleting GCS or Pparg in D2-MSNs causes depression-like behaviors in mice.

GlcCer and pioglitazone together show additive antidepressant effects.

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.

Figures