Infralimbic Cortex Microglial TREM-1 Mediates Neuroinflammation and Exacerbates Depressive-Like Behaviors in Parkinson's Disease Model Mice.

Depression is a common nonmotor feature of Parkinson's disease (PD) that severely compromises the quality of life of patients, yet its pathogenesis remains elusive. Triggering receptor expressed on myeloid cells 1 (TREM-1) is an immunoglobulin family receptor present on myeloid cells that amplifies neuroinflammatory cascades. However, the contribution of TREM-1 to the depressive-like behaviors associated with PD remains unclear. In a subacute model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) administered at a dose of 30 mg/kg/day for five consecutive days, we evaluated depressive-like behaviors and the expression of microglial TREM-1 in the infralimbic cortex (IL) on Days 3, 7, 14, and 21 following the final MPTP injection. Microglial TREM-1 expression in the IL peaked on Day 14, which coincided with the peak severity of depressive-like behaviors. Both genetic knockout and pharmacological blockade of TREM-1 attenuated proinflammatory cytokines production and reversed depressive-like behaviors. Together, these findings suggested that TREM-1 is a pivotal mediator of microglia-driven neuroinflammation and depression in PD model mice, underscoring its potential as a therapeutic target for nonmotor symptoms.