Disrupted betaine metabolism drives Th17 cell differentiation, mediating methamphetamine-induced depressive behaviors in male mice

Abstract Methamphetamine (METH) abuse, a global public health concern, is closely linked to neuropsychiatric disorders such as depression. Although the central nervous system (CNS) damage induced by METH is well documented, the role of peripheral immune mechanisms remains underexplored. To investigate this, we establish a depressive-like mouse model in male mice using repeated intraperitoneal METH injections. Behavioral tests, flow cytometry, RNA sequencing and metabolomics reveal the underlying mechanisms. METH exposure increases the differentiation of CD4⁺ T cells into Th17 cells in the spleen, likely driven by mitochondrial dysfunction and impaired betaine metabolism. These Th17 cells secrete elevated IL-17 A, which binds to IL-17RA on hippocampal CA1 neurons, activates the p38 MAPK signaling pathway, and disrupts synaptic plasticity. Interventions targeting Th17 cells or IL-17 A signaling significantly reduce depressive behavior. These findings uncover a novel peripheral immune mechanism in METH-related depression, wherein CD4⁺ T cell-derived IL-17 A contributes to hippocampal dysfunction via IL-17RA/p38 MAPK signaling. Targeting Th17 cells or IL-17 A may represent a promising therapeutic strategy for METH-associated neuropsychiatric disorders.