Dopamine depletion induces neuron-specific alterations of GABAergic transmission in the mouse striatum

Lack of dopamine (DA) in the striatum and the consequential dysregulation of thalamocortical circuits are major causes of motor impairments in Parkinson's disease. The striatum receives multiple cortical and subcortical afferents. Its role in movement control and motor skills learning is regulated by DA from the nigrostriatal pathway. In Parkinson's disease, DA loss affects striatal network activity and induces a functional imbalance of its output pathways, impairing thalamocortical function. Striatal projection neurons are GABAergic and form two functionally antagonistic pathways: the direct pathway, originating from DA receptor type 1-expressing medium spiny neurons (D₁ R-MSN), and the indirect pathway, from D₂ R-MSN. Here, we investigated whether DA depletion in mouse striatum also affects GABAergic function. We recorded GABAergic miniature IPSCs (mIPSC) and tonic inhibition from D₁ R- and D₂ R-MSN and used immunohistochemical labeling to study GABA_A R function and subcellular distribution in DA-depleted and control mice. We observed slower decay kinetics and increased tonic inhibition in D₁ R-MSN, while D₂ R-MSN had increased mIPSC frequency after DA depletion. Perisomatic synapses containing the GABA_A R subunits α₁ or α₂ were not affected, but there was a strong decrease in non-synaptic GABA_A Rs containing these subunits, suggesting altered receptor trafficking. To broaden these findings, we also investigated GABA_A Rs in GABAergic and cholinergic interneurons and found cell type-specific alterations in receptor distribution, likely reflecting changes in connectivity. Our results reveal that chronic DA depletion alters striatal GABAergic transmission, thereby affecting cellular and circuit activity. These alterations either result from pathological changes or represent a compensatory mechanism to counteract imbalance of output pathways.