Striatal Control of Movement: A Role for New Neuronal (Sub-) Populations?

Abstract

The striatum is a very heterogenous brain area, composed of different domains and compartments, albeit lacking visible anatomical demarcations. Two populations of striatal spiny projection neurons (SPNs) build the so-called direct and indirect pathway of the basal ganglia, whose coordinated activity is essential to control locomotion. Dysfunction of striatal SPNs is part of many movement disorders, such as Parkinson's disease (PD) and L-DOPA-induced dyskinesia. In this mini review article, I will highlight recent studies utilizing single-cell RNA sequencing to investigate the transcriptional profiles of striatal neurons. These studies discover that SPNs carry a transcriptional signature, indicating both their anatomical location and compartmental identity. Furthermore, the transcriptional profiles reveal the existence of additional distinct neuronal populations and previously unknown SPN sub-populations. In a parallel development, studies in rodent models of PD and L-DOPA-induced dyskinesia (LID) report that direct pathway SPNs do not react uniformly to L-DOPA therapy, and that only a subset of these neurons is underlying the development of abnormal movements. Together, these studies demonstrate a new level of cellular complexity for striatal (dys-) function and locomotor control.

Keywords: L-DOPA-induced dyskinesia; Parkinson’s disease; movement; scRNAseq; single-cell RNA sequencing; spiny projection neuron; striatum.

Figure 1

Striatal heterogeneity, spiny projection neuron (SPN) (sub-) populations and L-DOPA-induced dyskinesia (LID)-associated dSPNs. (A) The rodent striatum constitutes a complex, overlapping field of heterogeneity. It combines anatomic-functional domains, patch/matrix compartmentalization, and the “classical” distinction of dSPNs and iSPNs, which anchor the direct and indirect pathway of the basal ganglia. (B) Apart from “classical” SPNs, also D1/D2-SPNs were described in scRNA-seq studies, as well as new sub-populations. Characteristic genes are given in parentheses. (C) Three different studies identified a sub-group of dSPNs specifically linked to LID. The sub-group was either identified by Fos-TRAP, high-firing activity that correlates with LID, or a specific cellular phenotype. It is tempting to speculate that these three markers identified the same LID-linked subgroup of dSPNs.