Distinct contributions of two subpopulations of subthalamic neurons to levodopa-induced dyskinesia

The subthalamic nucleus (STN) is a prominent target for deep-brain stimulation (DBS) in the treatment of levodopa-induced dyskinesia (LID), a common motor complication of Parkinson's disease. However, the precise impact of STN-DBS on LID remains unclear. Here, we investigated the functional roles of two distinct neuronal populations within the STN in regulating LID. In a mouse model of LID, STN neurons projecting to the entopeduncular nucleus (EP) exhibited a U-shaped activation pattern, whereas those projecting to the tegmental reticular nucleus (RtTg) displayed a predominantly inhibitory response. Activation of EP-projecting STN neurons alleviated dyskinesia but worsened hypokinesia in the parkinsonian state. Activation of RtTg-projecting STN neurons alone did not induce hyperkinetic characteristics, except when combined with levodopa. These findings reveal two anatomically and functionally distinct populations of STN neurons involved in LID regulation, offering insights into the circuitry underlying STN-DBS.