Cell type-specific distribution of GABA_A receptor subtypes in the mouse dorsal striatum

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 GABA_A receptor (GABA_A R) subtypes, distinguished by their subunit composition, in striatal synapses. Here, by using immunofluorescence in mouse tissue, we investigated the distribution of GABA_A Rs containing the α₁ , α₂ , or α₃ subunit in perisomatic synapses of striatal MSN and interneurons, as well as the innervation pattern of D₁ R- and D₂ R-MSN soma and axonal initial segment (AIS) by GABAergic and cholinergic interneurons. Our results show that perisomatic GABAergic synapses of D₁ R- and D₂ R-MSN contain the GABA_A R α₁ and/or α₂ subunits, but not the α₃ subunit; D₂ R-MSN have significantly more α₁ -GABA_A Rs on their soma than D₁ R-MSN. Further, interneurons have few perisomatic synapses containing α₂ -GABA_A Rs, whereas α₃ -GABA_A Rs (along with the α₁ -GABA_A Rs) 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 GABA_A R subtypes.