Striatal lateral inhibition regulates action selection in a mouse model of levodopa-induced dyskinesia

Striatal medium spiny neurons (MSNs) integrate convergent cortical, thalamic, and dopaminergic inputs to shape motor output. In addition, MSNs form local inhibitory synaptic connections with one another. The function of this striatal lateral inhibition is unknown, but one possibility is in selecting an intended action while suppressing alternatives. The execution of selected movements is disrupted in several movement disorders, including levodopa-induced dyskinesia (LID), a complication of Parkinsons disease (PD) therapy characterized by involuntary movements. Here, we identify chronic changes in the strength of striatal lateral inhibitory synapses in a mouse model of PD/LID. These synapses are also modulated by acute dopamine signaling. Chemogenetic suppression of lateral inhibition originating from dopamine D2 receptor-expressing MSNs lowers the threshold to develop involuntary movements in vivo. By comparing striatal lateral inhibition in health and PD/LID, our findings support a role for this microcircuit in movement selection and suggest its disruption may increase vulnerability to dyskinesia.