The striatum is the main input nucleus of the basal ganglia, mediating motor and cognitive functions. Striatal projection neurons are GABAergic medium spiny neurons (MSN), expressing either the dopamine receptor type 1 (D1‐R MSN) and forming the direct, movement‐promoting pathway, or dopamine receptor type 2 (D2‐R MSN), forming the indirect movement‐suppressing pathway. Locally, activity and synchronization of MSN are modulated by several subtypes of GABAergic and cholinergic interneurons. Overall, GABAergic circuits in the striatum remain poorly characterized, and little is known about the intrastriatal connectivity of interneurons and the distribution of GABAA receptor (GABAAR) subtypes, distinguished by their subunit composition, in striatal synapses. Here, by using immunofluorescence in mouse tissue, we investigated the distribution of GABAARs containing the α1, α2, or α3 subunit in perisomatic synapses of striatal MSN and interneurons, as well as the innervation pattern of D1R‐ and D2R‐MSN soma and axonal initial segment (AIS) by GABAergic and cholinergic interneurons. Our results show that perisomatic GABAergic synapses of D1R‐ and D2R‐MSN contain the GABAAR α1 and/or α2 subunits, but not the α3 subunit; D2R‐MSN have significantly more α1‐GABAARs on their soma than D1R‐MSN. Further, interneurons have few perisomatic synapses containing α2‐GABAARs, whereas α3‐GABAARs (along with the α1‐GABAARs) are abundant in perisomatic synapses of CCK+, NPY+/SOM+, and vAChT+ interneurons. Each MSN and interneuron population analyzed received a distinct pattern of GABAergic and cholinergic innervation, complementing this postsynaptic heterogeneity. In conclusion, intra‐striatal GABAergic circuits are distinguished by cell‐type specific innervation patterns, differential expression and postsynaptic targeting of GABAAR subtypes.
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 (D 1 R-MSN), and the indirect pathway, from D 2 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 D 1 R-and D 2 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 D 1 R-MSN, while D 2 R-MSN had increased mIPSC frequency after DA depletion. Perisomatic synapses containing the GABA A R subunits α 1 or α 2 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.
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