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

Abstract

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 . Secondly, we characterized the detailed regional, cellular and subcellular expression of GABA (α , α , α , β , and γ ) and GABA (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 receptor subunits α , α , β , γ , and GABA receptor subunits R1 and R2. However, no expression of GABA receptor α subunit was detected. We also found a trend of increasing regional staining intensity for all positive GABA receptor subunits from the dorsolateral pole to ventromedial extremities. The GAD interneurons showed relatively low expression of GABA 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 and GABA receptors on subthalamic principal neurons.

Topographic connectivity and cellular profiling reveal detailed input pathways and functionally distinct cell types in the subthalamic nucleus

“…Notably, quantitative analysis of the topographic distribution of Pvalb + neurons indicated that glutamatergic PV+ neurons were particularly prevalent in the dorsolateral and middle STN ( Figure 4C, D ). Our serial multiplex-smFISH data provide direct evidence that PV+ STN cells are glutamatergic with topographic segregation in the STN (Hontanilla et al, 1998; Wu et al, 2018) and suggest that parvalbumin cannot reliably serve as a marker for GABAergic interneurons, together with previous findings (Jinno and Kosaka, 2004; Shang et al, 2015; Wallace et al, 2017).…”

“…Thus, our serial smFISH, immunostaining, and topographic analysis confirmed that most neurons in the STN are purely glutamatergic. Previous anatomical studies have reported the presence of parvalbumin-expressing (PV+) neurons in the STN (Alkemade et al, 2019; Hontanilla et al, 1998; Lévesque and Parent, 2005; Wu et al, 2018). PV expression is conventionally interpreted to reflect a GABAergic subpopulation (Hu et al, 2014), which is inconsistent with our serial smFISH results and previous studies (Lévesque and Parent, 2005; Roccaro-Waldmeyer et al, 2018).…”

“…Previous studies suggested the existence of glutamatergic PV+ neurons in STN and their topographical organization at coarse level (Hontanilla et al, 1998; Roccaro-Waldmeyer et al, 2018; Wu et al, 2018) based on immunohistochemistry with anti-PV or indirect comparison of separate conventional in situ hybridization datasets for PV and vGluT2, which makes it difficult to map a precise topographic distribution of STN PV+ neurons. Here, we directly identified topographically localized glutamatergic PV+ neurons in the STN using serial multiplex smFISH.…”

Coexistence of Lambert–Eaton myasthenic syndrome and autoimmune encephalitis with anti-CRMP5/CV2 and anti-GABAB receptor antibodies in small cell lung cancer

“…GABA B receptors are mainly located in the presynaptic and postsynaptic regions of synapses in the hippocampus, thalamus, and cerebellum. [ 14 , 15 ] Mice lacking GABA B receptors develop epilepsy and deficits in memory, learning, and behavior. [ 2 – 6 ] Qiao et al [ 2 ] and Cui et al [ 4 ] have reported that, in China, patients with anti-GABA B receptor encephalitis are mainly male and have a median age at presentation of 60 years.…”

Differential ultrastructural alterations in the Vglut2 glutamatergic input to the substantia nigra pars compacta/pars reticulata following nigrostriatal dopamine loss in a progressive mouse model of Parkinson’s disease

“…Although there are no direct data supporting this later hypothesis, it is possible that there is differential localization of various presynaptic receptors on Vglut2+ terminals within the SNpc versus SNpr that could variably regulate the release of glutamate. It has been reported that there are various presynaptic receptors located on STN terminals, such as the cannabinoid (Sánchez‐Zavaleta et al., 2018) and GABA (Wu, Song, Faull, & Waldvogel, 2018), making it possible that these receptors are differentially distributed within various neurons of the STN.…”