The external globus pallidus: progress and perspectives

Abstract

The external globus pallidus (GPe) of the basal ganglia is in a unique and powerful position to influence processing of motor information by virtue of its widespread projections to all basal ganglia nuclei. Despite the clinical importance of the GPe in common motor disorders such as Parkinson's disease, there is only limited information about its cellular composition and organizational principles. In this review, recent advances in the understanding of the diversity in the molecular profile, anatomy, physiology and corresponding behaviour during movement of GPe neurons are described. Importantly, this study attempts to build consensus and highlight commonalities of the cellular classification based on existing but contentious literature. Additionally, an analysis of the literature concerning the intricate reciprocal loops formed between the GPe and major synaptic partners, including both the striatum and the subthalamic nucleus, is provided. In conclusion, the GPe has emerged as a crucial node in the basal ganglia macrocircuit. While subtleties in the cellular makeup and synaptic connection of the GPe create new challenges, modern research tools have shown promise in untangling such complexity, and will provide better understanding of the roles of the GPe in encoding movements and their associated pathologies.

Keywords: Npas1; Parkinson's disease; arkypallidal neurons; parvalbumin; prototypic neurons.

Figure 1. Diagrams summarizing the classification of GPe neurons

(a) Six different GPe neuron classes are identified based on the expression of various molecular markers. For consistency, only gene names are used throughout (though for readability they are not italicized). Plus and minus signs denote positive and negative-expression, respectively. Alternative names are listed below to cross reference with the main text. Percentages given are only approximations because of the ranges in the results reported in the literature. The relative numbers of different classes of GPe neurons listed is a deduction based on comparative analysis across several experimental findings in Abdi et al. (2015), Dodson, et al. (2015), and Hernández et al. (2015). Though it is clear that a unique class of Lhx6⁺ neurons exist, there is evidence for the expression of Lhx6 in multiple classes of GPe neurons. The field has yet to come to a consensus on the abundance and origin of Lhx6⁺ GPe neurons. In contrast, it is now well-established that Npas1⁺ GPe neurons and Pvalb⁺ GPe neurons form two distinct classes that project heavily to the dorsal striatum and subthalamic nucleus, respectively. Their relationships with arkypallidal GPe neurons and prototypic GPe neurons are illustrated in (b). See Table 1 for further description on their electrophysiological characteristics. (b) Four unique GPe neuron classes are identified so far based on the molecular signature, electrophysiological characteristics, projection patterns, and developmental origins. An additional list of molecular markers are listed for arkypallidal neurons and prototypic neurons. Prototypic neurons are more broadly defined in the literature than in the figure, which highlights the most well-defined subclass. Alternative names: Chat, ChAT, choline acetyltransferase; dStr, dorsal striatum; Etv1, ER81; GPe, external globus pallidus; LGE, lateral ganglionic eminence; MGE, medial ganglionic eminence; Penk, PPE, preproenkephalin; PoA, preoptic area; Pvalb, PV, parvalbumin; STN, subthalamic nucleus.