GABA_A and GABA_B receptor subunit localization on neurochemically identified neurons of the human subthalamic nucleus

The subthalamic nucleus (STN) is a critical excitatory signaling center within the basal ganglia circuitry. The activity of subthalamic neurons is tightly controlled by upstream inhibitory signaling centers in the basal ganglia. In this study, we used immunohistochemical techniques to firstly, visualize and quantify the STN neurochemical organization based on neuronal markers including parvalbumin (PV), calretinin (CR), SMI-32, and GAD_65/67 . Secondly, we characterized the detailed regional, cellular and subcellular expression of GABA_A (α₁ , α₂ , α₃ , β_2/3 , and γ₂ ) and GABA_B (R1 and R2) receptor subunits within the normal human STN. Overall, we found seven neurochemically distinct populations of principal neurons in the human STN. The three main populations detected were: (a) triple-labeled PV⁺ /CR⁺ /SMI32⁺ ; (b) double-labeled PV⁺ /CR⁺ ; and (c) single-labeled CR⁺ neurons. Subthalamic principal neurons were found to express GABA_A receptor subunits α₁ , α₃ , β_2/3 , γ₂ , and GABA_B receptor subunits R1 and R2. However, no expression of GABA_A receptor α₂ subunit was detected. We also found a trend of increasing regional staining intensity for all positive GABA_A receptor subunits from the dorsolateral pole to ventromedial extremities. The GAD⁺ interneurons showed relatively low expression of GABA_A receptor subunits. These results provide the morphological basis of GABAergic transmission within the normal human subthalamic nucleus and evidence of GABA innervation through both GABA_A and GABA_B receptors on subthalamic principal neurons.