Dysregulation of striatal projection neurons in Parkinson's disease

Abstract

The loss of nigrostriatal dopamine (DA) is the primary cause of motor dysfunction in Parkinson's disease (PD), but the underlying striatal mechanisms remain unclear. In spite of abundant literature portraying structural, biochemical and plasticity changes of striatal projection neurons (SPNs), in the past there has been a data vacuum from the natural human disease and its close model in non-human primates. Recently, single-cell recordings in advanced parkinsonian primates have generated new insights into the altered function of SPNs. Currently, there are also human data that provide direct evidence of profoundly dysregulated SPN activity in PD. Here, we review primate recordings that are impacting our understanding of the striatal dysfunction after DA loss, particularly through the analysis of physiologic correlates of parkinsonian motor behaviors. In contrast to recordings in rodents, data obtained in primates and patients demonstrate similar major abnormalities of the spontaneous SPN firing in the alert parkinsonian state. Furthermore, these studies also show altered SPN responses to DA replacement in the advanced parkinsonian state. Clearly, there is yet much to learn about the striatal discharges in PD, but studies using primate models are contributing unique information to advance our understanding of pathophysiologic mechanisms.

Keywords: Direct and indirect pathways; Dyskinesia; Non-human primates; Parkinson’s disease; Striatal projection neurons.

Fig. 1

Schematic representation of the basal ganglia circuitry. The simplified scheme depicts the functional alterations that follow DA loss in Parkinson’s disease according to the classic model. The broken yellow arrow represents nigrostriatal DA loss. The direct and indirect striatal output pathways are hypoactive and hyperactive, according to the loss of D1R or D2R receptor regulation, respectively. Red and green arrows are glutamatergic and GABAergic connections. Increase and decrease activity are represented by thick, solid or thin, broken arrows, respectively. GPe and GPi globus pallidus external and internal segments, STN subthalamic nucleus, SNc substantia nigra pars compacta

Fig. 2

Comparison of the SPN activity in NHP between normal and advanced parkinsonian conditions. The examples show: top trace of the spike train with the raster of single units produced after spike sorting placed above the trace and the waveform below; middle firing frequency over time, and bottom ISI (inter-spike interval) distribution over time. The two examples show the typical large differences in the SPN firing that is significantly increased in the parkinsonian state (Liang et al. 2008)

Fig. 3

Changes of the SPN activity in response to DA. Changes in SPN firing frequencies across motor states are grouped by type of response “stability” or “inversion”. The mean firing frequencies are depicted in the transition to motor states induced by levodopa administration (s.c.) in the parkinsonian NHP (“off”, “on”, and “Dyskinesias” states). Top the graphs show SPN groups responding with activity increase in the “on” state (D1R-like response). Bottom the graphs show SPN groups responding with activity decrease in the “on” state (D2R-like response). Each curve represents firing frequencies of a single neuron in the transition to motor states with differences that are statistically significant at p < 0.01 or lower (error bars are omitted) (Liang et al. 2008; Singh et al. 2015)

Fig. 4

Imbalance of SPN responses to DA associated with dyskinesias. The averaged frequency changes of SPN grouped according to their responses are computed. The percentage of frequency change during the “on” and “dyskinesias” states with respect to the “off” state (baseline) is plotted in each group of responses shown as solid and dotted lines for stable and inverted responses, respectively. A loss of balance ‘within’ each SPN subpopulation (D1R- and D2R-mediated activity increase and decrease in the “on” state) occurs with dyskinesias (*p < 0.001 vs. previous state)

Fig. 5

Comparison of the human SPN activity between essential tremor and PD. The upper examples show (top) traces of the spike train with the raster of single units produced after spike sorting placed above the trace and the waveform below, and (bottom) the firing frequency over time. These two examples show the typical large differences in the SPN firing that is significantly increased in patients with Parkinson’s disease. The bottom graphs show averaged SPN firing frequencies. Left increase of SPN activity from normal to parkinsonian MPTP-treated NHPs. Right similar SPN activity increase between patients with essential tremor and PD (Singh et al. 2016)