Serotonergic control of the glutamatergic neurons of the subthalamic nucleus

Abstract

The subthalamic nucleus (STN) houses a dense cluster of glutamatergic neurons that play a central role in the functional dynamics of the basal ganglia, a group of subcortical structures involved in the control of motor behaviors. Numerous anatomical, electrophysiological, neurochemical and behavioral studies have reported that serotonergic neurons from the midbrain raphe nuclei modulate the activity of STN neurons. Here, we describe this serotonergic innervation and the nature of the regulation exerted by serotonin (5-hydroxytryptamine, 5-HT) on STN neuron activity. This regulation can occur either directly within the STN or at distal sites, including other structures of the basal ganglia or cortex. The effect of 5-HT on STN neuronal activity involves several 5-HT receptor subtypes, including 5-HT_1A, 5-HT_1B, 5-HT_2C and 5-HT₄ receptors, which have garnered the highest attention on this topic. The multiple regulatory effects exerted by 5-HT are thought to be modified under pathological conditions, altering the activity of the STN, or due to the benefits and side effects of treatments used for Parkinson's disease, notably the dopamine precursor l-DOPA and high-frequency STN stimulation. Originally understood as a motor center, the STN is also associated with decision making and participates in mood regulation and cognitive performance, two domains of personality that are also regulated by 5-HT. The literature concerning the link between 5-HT and STN is already important, and the functional overlap is evident, but this link is still not entirely understood. The understanding of this link between 5-HT and STN should be increased due to the possible importance of this regulation in the control of fronto-STN loops and inherent motor and non-motor behaviors.

Introduction

The subthalamic nucleus (STN) is a small, dense nucleus that plays an important role in the control of motor behaviors. The STN is believed to act as a “driving force” in fixing and organizing information conveyed by the cortex to the basal ganglia, a group of functionally associated subcortical structures to which the STN belongs along with the striatum, the substantia nigra (SN), and the globus pallidus (GP). This peculiarity is in part related to its neuronal composition, which exclusively includes glutamatergic neurons that mainly contact the GABAergic neurons of the SN and the GP. The importance of the STN in the control of motor behaviors is highlighted in the treatment of Parkinson's disease (PD), in which the surgical, stereotaxic placement of electrodes in the STN and the subsequent high-frequency stimulation (HFS or deep brain stimulation DBS) of these electrodes remains one of the best approaches for Parkinsonian patients (Benabid et al., 1998; Faggiani and Benazzouz, 2017; Krack et al., 1999; Limousin et al., 1995, Limousin et al., 1998). HFS of the STN has also been adapted with some success to other diseases, including obsessional compulsive disorders (OCD) (Welter et al., 2011).

The serotonergic neurons innervate the basal ganglia, and it is noteworthy that the highest densities of serotonin (5-HT) fibers and 5-HT content in the brain are found in the SN and ventral tegmental area, and these fibers and contents are also elevated in the STN. The STN neurons express various 5-HT receptors that can follow their axons in the GP or SN, while afferent fibers can also express presynaptic 5-HT receptors. Preclinical evidence supports a direct or indirect role of 5-HT_1A, 5-HT_1B, 5-HT_2C and 5-HT₄ receptors in the control of STN neuronal activity. The link between these regulatory mechanisms and behavioral outputs is not always clear due to some controversies regarding the influence of a given 5-HT receptor on STN neuronal activity.

In this chapter, we summarize the data concerning the influence of 5-HT on the function of the STN. We will first consider the location of the STN within the basal ganglia and then describe the anatomical organization of the 5-HT systems in the STN. Thereafter, we will present electrophysiological, neurochemical, neuroimaging, and some behavioral data that highlight the influence of 5-HT and 5-HT receptors on STN function. These data will allow us to discuss the nature of 5-HT-mediated regulation in the physiopathology of PD, OCD, or drug addiction and the HFS effect of the STN, in the last section. Notably, most of the data are preclinical evidence, and 5-HT-mediated regulation of the STN has still not been considered for developing new therapeutic strategies for brain diseases.