Comparative Ultrastructural Analysis of Thalamocortical Innervation of the Primary Motor Cortex and Supplementary Motor Area in Control and MPTP-Treated Parkinsonian Monkeys

Abstract

The synaptic organization of thalamic inputs to motor cortices remains poorly understood in primates. Thus, we compared the regional and synaptic connections of vGluT2-positive thalamocortical glutamatergic terminals in the supplementary motor area (SMA) and the primary motor cortex (M1) between control and MPTP-treated parkinsonian monkeys. In controls, vGluT2-containing fibers and terminal-like profiles invaded layer II–III and Vb of M1 and SMA. A significant reduction of vGluT2 labeling was found in layer Vb, but not in layer II–III, of parkinsonian animals, suggesting a potential thalamic denervation of deep cortical layers in parkinsonism. There was a significant difference in the pattern of synaptic connectivity in layers II–III, but not in layer Vb, between M1 and SMA of control monkeys. However, this difference was abolished in parkinsonian animals. No major difference was found in the proportion of perforated versus macular post-synaptic densities at thalamocortical synapses between control and parkinsonian monkeys in both cortical regions, except for a slight increase in the prevalence of perforated axo-dendritic synapses in the SMA of parkinsonian monkeys. Our findings suggest that disruption of the thalamic innervation of M1 and SMA may underlie pathophysiological changes of the motor thalamocortical loop in the state of parkinsonism.

Cell Type-Specific Decrease of the Intrinsic Excitability of Motor Cortical Pyramidal Neurons in Parkinsonism

“…For example, recent studies highlighted a critical role of indirect pathway striatal projection neurons in driving cellular and synaptic adaptations in basal ganglia nuclei in parkinsonism, such as the subthalamic nucleus (Chu et al, 2017;Sharott et al, 2017;Ryan et al, 2018;McIver et al, 2019). Similarly, pathologic basal ganglia outputs in parkinsonism can drive adaptive changes in M1 via the thalamocortical projections (Villalba et al, 2021).…”

Reduced Thalamic Excitation to Motor Cortical Pyramidal Tract Neurons in a Mouse Model of Parkinsonism

“…The density of vGluT2-ir puncta was significantly decreased in slices from 6-OHDA mice relative to those from controls (control = 20.4 [16.9–22.9] million puncta/mm 3 , n = 20 slices/3 mice; 6-OHDA = 11.2 [8.5–13.9] million puncta/mm 3 , n = 20 slices/3 mice; p < 0.0001, MWU; Figure 3A-C ). These data are consisted with findings from MPTP-treated NHP (Villalba et al, 2021). It has been reported that reduced vGluTs levels per terminal leads to a smaller vesicle size (Wojcik et al, 2004).…”

“…Thalamic axon terminals target the dendritic spines and dendritic shaft of M1 PT neurons (Hooks et al, 2013;Kuramoto et al, 2009;Villalba et al, 2021). To interrogate postsynaptic structural changes associated with DA degeneration, the density of dendritic spines and the diameter of dendritic shaft of M1 PT neurons were assessed in slices from controls and 6-OHDA mice that received AAVrg-hSyn-eGFP injections into the pontine nuclei (Figure 3D, E).…”

“…A large body of evidence in literature suggests M1 circuitry dysfunction in parkinsonism. Degeneration of SNc DA neurons impairs motor skills and decreases forelimb representation in the M1 of rodents (Brown et al, 2009; Plowman et al, 2011; Viaro et al, 2011), which perhaps involve intrinsic and synaptic adaptations in M1 associated with DA depletion (Aeed et al, 2021; Cousineau et al, 2020; Guo et al, 2015b; Villalba et al, 2021). Consistently, M1 pyramidal neurons exhibit enhanced bursting pattern of activity and synchronization following chronic DA degeneration (Aeed et al, 2021; Goldberg et al, 2002; Pasquereau and Turner, 2011; Pasquereau et al, 2016).…”

“…A growing amount of evidence suggests that M1 circuits exhibit specific alterations in parkinsonism. Loss of SNc DA neurons alters neuronal firing and synaptic connectivity of M1 pyramidal neurons (12,(23)(24)(25). Particularly, DA depletion selectively affects the activity of pyramidal tract (PT) neurons, but not the intratalencephalic (IT) neurons, in the layer (L) 5 of M1 (12,14,21,22,26,27).…”