Cell-specific pallidal intervention induces long-lasting motor recovery in dopamine-depleted mice

Mastro, Kevin J; Zitelli, Kevin T.; Willard, Amanda M; LeBlanc, Kimberly H.; Kravitz, Alexxai V.; Gittis, Aryn H.

doi:10.1038/nn.4559

Cited by 141 publications

(143 citation statements)

References 52 publications

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“…It remains to be determined whether prevention of hyperdirect pathway downregulation or disconnection of the indirect pathway or the combination of these effects contributes to improved motor function. Certainly, GPe-STN neurons appear to be critical for the expression of motor dysfunction, as evinced by the persistent therapeutic effect of their selective optogenetic stimulation in PD mice (Mastro et al, 2017). …”

Section: Discussionmentioning

confidence: 99%

Loss of Hyperdirect Pathway Cortico-Subthalamic Inputs Following Degeneration of Midbrain Dopamine Neurons

Chu

McIver

Kovaleski

et al. 2017

Neuron

109

181

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SUMMARY The motor symptoms of Parkinson’s disease (PD) are linked to abnormally correlated and coherent activity in the cortex and subthalamic nucleus (STN). However, in parkinsonian mice we found that cortico-STN transmission strength had diminished by 50–75% through loss of axo-dendritic and axo-spinous synapses, was incapable of long-term potentiation, and less effectively patterned STN activity. Optogenetic, chemogenetic, genetic, and pharmacological interrogation suggested that downregulation of cortico-STN transmission in PD mice was triggered by increased striato-pallidal transmission, leading to disinhibition of the STN and increased activation of STN NMDA receptors. Knockdown of STN NMDA receptors, which also suppresses proliferation of GABAergic pallido-STN inputs in PD mice, reduced loss of cortico-STN transmission and patterning, and improved motor function. Together, the data suggest that loss of dopamine triggers a maladaptive shift in the balance of synaptic excitation and inhibition in the STN, which contributes to parkinsonian activity and motor dysfunction.

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Section: Discussionmentioning

confidence: 99%

Loss of Hyperdirect Pathway Cortico-Subthalamic Inputs Following Degeneration of Midbrain Dopamine Neurons

Chu

McIver

Kovaleski

et al. 2017

Neuron

109

181

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“…An important recent insight has changed this concept by showing that GPe neurons are, in fact, heterogeneous, belonging to at least two major classes, that is, “arkypallidal” neurons that project to the striatum and “prototypical” neurons, which project to the STN, GPi, and SNr. In rodents, molecular differences among GPe neurons have been used to genetically target and manipulate these neuron subtypes using optogenetic and pharmacogenetic techniques . It is not clear whether and how these protein expression patterns translate to the primate GPe.…”

Section: Evolving Topicsmentioning

confidence: 99%

“…Although this may play a role in normal basal ganglia function(s), the role of these cells in parkinsonism is not known . Recent optogenetic and pharmacogenetic studies in parkinsonian rodents have suggested that selective activation of arkypallidal neurons may be detrimental whereas selective activation of prototypical neurons can produce antiparkinsonian effects . It remains to be seen whether similarly specific manipulations can lead to antiparkinsonian effects in nonhuman primates or patients with PD, without the risk of inducing dyskinesias.…”

Section: Evolving Topicsmentioning

confidence: 99%

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Changing views of the pathophysiology of Parkinsonism

Wichmann

2019

Movement Disorders

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Studies of the pathophysiology of parkinsonism (specifically akinesia and bradykinesia) have a long history and primarily model the consequences of dopamine loss in the basal ganglia on the function of the basal ganglia/thalamocortical circuit(s). Changes of firing rates of individual nodes within these circuits were originally considered central to parkinsonism. However, this view has now given way to the belief that changes in firing patterns within the basal ganglia and related nuclei are more important, including the emergence of burst discharges, greater synchrony of firing between neighboring neurons, oscillatory activity patterns, and the excessive coupling of oscillatory activities at different frequencies. Primarily focusing on studies obtained in nonhuman primates and human patients with Parkinson's disease, this review summarizes the current state of this field and highlights several emerging areas of research, including studies of the impact of the heterogeneity of external pallidal neurons on parkinsonism, the importance of extrastriatal dopamine loss, parkinsonism‐associated synaptic and morphologic plasticity, and the potential role(s) of the cerebellum and brainstem in the motor dysfunction of Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society

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“…Prior studies in the field have suggested GPe neuron subtypes are involved in some aspect of movement control (Dodson et al, 2015;Glajch et al, 2016;Mastro et al, 2017). However, precisely how these neuron subclasses are involved in motor function and dysfunction is poorly defined.…”

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confidence: 99%

Npas1⁺-Nkx2.1⁺Neurons Are an Integral Part of the Cortico-pallido-cortical Loop

Abecassis¹,

Berceau²,

Win³

et al. 2019

Preprint

108

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Within the basal ganglia circuit, the external globus pallidus (GPe) is critically involved in motor control. Aside from Foxp2+ neurons and ChAT+ neurons that have been established as unique neuron types, there is little consensus on the classification of GPe neurons. Properties of the remaining neuron types are poorly-defined. In this study, we leverage new mouse lines, viral tools, and molecular markers to better define GPe neuron subtypes. We found that Sox6 represents a novel, defining marker for GPe neuron subtypes. Lhx6+ neurons that lack the expression of Sox6 were devoid of both parvalbumin and Npas1. This result confirms previous assertions of the existence of a unique Lhx6+ population. Neurons that arise from the Dbx1+ lineage were similarly abundant in the GPe and displayed a heterogeneous makeup. Importantly, tracing experiments revealed that Npas1+-Nkx2.1+ neurons represent the principal non-cholinergic, cortically-projecting neurons. In other words, they form the pallido-cortical arm of the cortico-pallido-cortical loop. Our data further described that pyramidal-tract neurons in the cortex collateralized within the GPe, forming a closed-loop system between the two brain structures. Overall, our findings reconcile some of the discrepancies that arose from differences in techniques or the reliance on pre-existing tools. While spatial distribution and electrophysiological properties of GPe neurons reaffirm the diversification of GPe subtypes, statistical analyses strongly support the notion that these neuron subtypes can be categorized under the two principal neuron classes—i.e., PV+ neurons and Npas1+ neurons.Significance statementThe poor understanding of the neuronal composition in the GPe undermines our ability to interrogate its precise behavioral and disease involvements. In this study, twelve different genetic crosses were used, hundreds of neurons were electrophysiologically-characterized, and over 100,000 neurons were histologically- and/or anatomically-profiled. Our current study further establishes the segregation of GPe neuron classes and illustrates the complexity of GPe neurons in adult mice. Our results support the idea that Npas1+-Nkx2.1+ neurons are a distinct GPe neuron subclass. By providing a detailed analysis of the organization of the cortico-pallidal-cortical projection, our findings establish the cellular and circuit substrates that can be important for motor function and dysfunction.

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Cell-specific pallidal intervention induces long-lasting motor recovery in dopamine-depleted mice

Cited by 141 publications

References 52 publications

Loss of Hyperdirect Pathway Cortico-Subthalamic Inputs Following Degeneration of Midbrain Dopamine Neurons

Loss of Hyperdirect Pathway Cortico-Subthalamic Inputs Following Degeneration of Midbrain Dopamine Neurons

Changing views of the pathophysiology of Parkinsonism

Npas1⁺-Nkx2.1⁺Neurons Are an Integral Part of the Cortico-pallido-cortical Loop

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Cell-specific pallidal intervention induces long-lasting motor recovery in dopamine-depleted mice

Cited by 141 publications

References 52 publications

Loss of Hyperdirect Pathway Cortico-Subthalamic Inputs Following Degeneration of Midbrain Dopamine Neurons

Loss of Hyperdirect Pathway Cortico-Subthalamic Inputs Following Degeneration of Midbrain Dopamine Neurons

Changing views of the pathophysiology of Parkinsonism

Npas1+-Nkx2.1+Neurons Are an Integral Part of the Cortico-pallido-cortical Loop

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Npas1⁺-Nkx2.1⁺Neurons Are an Integral Part of the Cortico-pallido-cortical Loop