Parvalbumin+ Neurons and Npas1+ Neurons Are Distinct Neuron Classes in the Mouse External Globus Pallidus

Abstract

Compelling evidence suggests that pathological activity of the external globus pallidus (GPe), a nucleus in the basal ganglia, contributes to the motor symptoms of a variety of movement disorders such as Parkinson's disease. Recent studies have challenged the idea that the GPe comprises a single, homogenous population of neurons that serves as a simple relay in the indirect pathway. However, we still lack a full understanding of the diversity of the neurons that make up the GPe. Specifically, a more precise classification scheme is needed to better describe the fundamental biology and function of different GPe neuron classes. To this end, we generated a novel multicistronic BAC (bacterial artificial chromosome) transgenic mouse line under the regulatory elements of the Npas1 gene. Using a combinatorial transgenic and immunohistochemical approach, we discovered that parvalbumin-expressing neurons and Npas1-expressing neurons in the GPe represent two nonoverlapping cell classes, amounting to 55% and 27% of the total GPe neuron population, respectively. These two genetically identified cell classes projected primarily to the subthalamic nucleus and to the striatum, respectively. Additionally, parvalbumin-expressing neurons and Npas1-expressing neurons were distinct in their autonomous and driven firing characteristics, their expression of intrinsic ion conductances, and their responsiveness to chronic 6-hydroxydopamine lesion. In summary, our data argue that parvalbumin-expressing neurons and Npas1-expressing neurons are two distinct functional classes of GPe neurons. This work revises our understanding of the GPe, and provides the foundation for future studies of its function and dysfunction.

Inhibitory Control in the Cortico-Basal Ganglia-Thalamocortical Loop: Complex Regulation and Interplay with Memory and Decision Processes

“…We found that the SSRT can be effectively modulated by some specific intrinsic BG connections, in particular the newly discovered pathway from the external segment of the globus pallidus (GPe) to the striatum (Abdi et al, 2015; Dodson et al, 2015; Hegeman et al, 2016; Hernandez et al, 2015; Mallet et al, 2012) plays an essential role in cancelling a planned response in midcourse, in support of the recent physiological report (Mallet et al, 2016). The thalamocortical connection exerts a two-level modulation of SSRT by switching the distributed attractor network between states with or without persistent activity.…”

Double In situ Hybridization for MicroRNAs and mRNAs in Brain Tissues

“…Subsequently, we detected each probe using the TSA system in series. As shown in Figure 7, miR-34a signals were co-localized with PV signals in the TRN, the globus pallidus and the entopeduncular nucleus, where GABAergic neurons are localized (Hernández et al, 2015). ISH using the sense probe of PV mRNA did not detect any ISH signals (data not shown).…”

Blunted mGluR Activation Disinhibits Striatopallidal Transmission in Parkinsonian Mice

“…This process could be important for encoding functional segregation of movements within the GPe (Hegeman et al, 2016; Jin et al, 2014; Shi et al, 2004; Turner and Anderson, 2005). The pathophysiology of PD can be explained by the changes in the activity levels and synchrony in the GPe (Bergman et al, 1998; Chan et al, 2011; Hegeman et al, 2016; Hernandez et al, 2015; Kita and Kita, 2011). In a normal state, individual GPe neurons respond specifically to the movement in one direction of a single joint on the contralateral side.…”