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

<b>Rationale:</b> 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. <b>Methods:</b> 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 <i>Pparg</i> 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. <b>Results:</b> 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 <i>Pparg</i> 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. <b>Conclusions:</b> 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.