Connectivity and Functionality of the Globus Pallidus Externa Under Normal Conditions and Parkinson's Disease

Abstract

The globus pallidus externa (GPe) functions as a central hub in the basal ganglia for processing motor and non-motor information through the creation of complex connections with the other basal ganglia nuclei and brain regions. Recently, with the adoption of sophisticated genetic tools, substantial advances have been made in understanding the distinct molecular, anatomical, electrophysiological, and functional properties of GPe neurons and non-neuronal cells. Impairments in dopamine transmission in the basal ganglia contribute to Parkinson's disease (PD), the most common movement disorder that severely affects the patients' life quality. Altered GPe neuron activity and synaptic connections have also been found in both PD patients and pre-clinical models. In this review, we will summarize the main findings on the composition, connectivity and functionality of different GPe cell populations and the potential GPe-related mechanisms of PD symptoms to better understand the cell type and circuit-specific roles of GPe in both normal and PD conditions.

Keywords: Parkinson's disease; arkypallidal neurons; basal ganglia; dopaminergic neurons; glia; globus pallidus externa; prototypic neurons.

Figure 1

Location and cellular distribution of GPe in mouse brain. (A) Sagittal scheme showing the locations of BG nuclei (dark gray) and other subregions in the brain. The GPe is located in the central BG. (B) Location of GPe (inset) and spatial distribution of GPe subpopulations at the coronal level. BG, basal ganglia; DRN, dorsal raphe nucleus; EPN, entopeduncular nucleus; GPe, globus pallidus externa; Lhx6, LIM homeobox 6; PPN, pedunculopontine nucleus; PV, Parvalbumin; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; STN, subthalamic nucleus. The template of brain atlas was obtained from Allen Mouse Brain Atlas.

Figure 2

GPe neuron composition. Pie chart summarizing the GPe neuronal composition and general overlapping relationships among different molecular markers. The area of each marker represents the approximate percentage of each subpopulation. FoxP2+, Forkhead box protein P2-positive; Lhx6+, LIM homeobox 6-positive; Nkx2.1+, Nk2 homeobox 1-positive; Npas1+, Neuronal PAS domain protein 1-positive.

Figure 3

Major inputs and outputs of GPe neuron subtypes. (A) GPe afferents from striatum, cortex, and STN. (B) GPe efferents to striatum, cortex and BG downstream nuclei. Thickness of line represent the intensity of projections. Dash line marks unconfirmed connections. Arrowhead represents excitatory projection. T-head depicts inhibitory projection. Ark, arkypallidal neurons; ChAT, choline acetyltransferase; Pro, prototypic neurons.

Figure 4

Changes of BG connectivity and neuron activity between normal and PD. (A) Complex functional connectivity and related neuron firing rate in normal condition. GPe receives the GABAergic projections from iSPNs and dSPNs (blue lines), the dopaminergic projections from SNc (green lines), and glutamatergic projections (red lines) from STN, cortex and thalamus. In normal condition, GPe neurons maintain their own firing rate; but in PD (B), due to the loss of dopaminergic inputs (green dash lines), several pathways have been altered greatly, either enhanced or weakened, resulting in abnormal firing rate or pattern of both GPe and its downstream nuclei, such as increase of β oscillation. Ark, arkypallidal neurons; ChAT, choline acetyltransferase; G (star), glia; ITN, interneurons; Pro, prototypic neurons.