Ultrastructural Plasticity of Pallidothalamic GABAergic Terminals in Parkinson’s Disease: A 3D Electron Microscopy Study in the Parvocellular Ventral Anterior and Centromedian Thalamic Nuclei in MPTP-Treated Parkinsonian Monkeys 公开

Kelly, Hannah (Spring 2019)

Permanent URL: https://etd.library.emory.edu/concern/etds/2z10wr27j?locale=zh
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Abstract

The internal globus pallidus (GPi) is the main source of basal ganglia GABAergic afferents to the parvocellular region of the ventral anterior nucleus (VApc) and the centromedian nucleus (CM) in the thalamus. Models of the basal ganglia-thalamocortical circuitry predict that nigrostriatal dopamine loss causes abnormally increased GABAergic pallidal outflow to the thalamus in Parkinson’s disease (PD). However, our understanding of the pathophysiology and underlying anatomical substrates of this increased pallidothalamic activity remains limited. Electrophysiological studies have reported complex changes in firing rates of thalamocortical neurons in animal models of parkinsonism and in PD patients. In the striatum and subthalamic nucleus, altered neuronal activity in the parkinsonian state is associated with structural changes in GABAergic and glutamatergic synapses. The GPi gives rise to large GABAergic terminals forming multiple axo-dendritic synapses in the VApc and CM. Functional data gathered from structurally-similar terminals in other regions suggests that the multi-synaptic morphology of GPi-like terminals creates favorable conditions for inter-synaptic spillover of GABA, which may enable tonic inhibition even under conditions of high presynaptic firing rates.

Understanding ultrastructural changes of pallidothalamic terminals will help elucidate the impact of altered GPi outflow onto thalamocortical neurons in parkinsonism. To address this, we used serial block-face scanning electron microscopy to quantitatively compare the morphology of GPi terminals in the VApc and CM of control and MPTP-treated parkinsonian monkeys. Preliminary results suggest that the following structural changes take place in parkinsonian animals: the volume of GPi terminals is enlarged in VApc and CM; the average number of synapses per terminal is decreased in VApc and increased in CM; and the surface areas of synapses formed by terminals are increased in VApc and CM. These findings indicate that pallidothalamic terminals are endowed with a high level of structural plasticity possibly contributing to increased tonic regulation of thalamocortical outflow in PD. Our data also demonstrate target-specific differences in the ultrastructure of GPi terminals that innervate VApc vs. CM neurons, which may underlie physiological differences in the effects of pallidal output to these thalamic targets.  

Table of Contents

INTRODUCTION: 1

Background: 1

General Organization of the Basal Ganglia: 1

Organization of the Basal Ganglia-Receiving Thalamic Nuclei: 3

CM/Pf Degeneration in PD: 4

Changes in the Rate and Patterns of Neuronal Activity in the Basal Ganglia-Thalamocortical Loop in PD: 5

Morphological and Structural Changes in the Pallidothalamic System in PD: 6

Multi-synaptic Arrangement of GPi and Other GABAergic Thalamic Terminals: 7

Serial Block-Face Scanning Electron Microscopy and 3D Reconstruction to Examine Ultrastructural Changes in Pallidothalamic Terminals of Parkinsonian Monkeys: 8

Study Goals: 9

MATERIALS AND METHODS: 10

Animals: 10

MPTP Treatment and Assessment of Parkinsonism: 10

Anterograde Labeling of Pallidothalamic Terminals: 11

Tissue Collection and Processing for Microscopy: 11

3D Reconstruction from Serial Section Electron Microscopy: 13

Statistical Analysis: 15

RESULTS: 15

Ultrastructural Features of Pallidothalamic Terminals in the VApc of a Control vs. MPTP-treated Parkinsonian Monkey: 15

Ultrastructural Features of Pallidothalamic Terminals in the CM of a Control and MPTP-treated monkey: 19

Comparison of Ultrastructural Features of Pallidothalamic Terminals between the VApc and CM of a Control and MPTP-treated Monkey: 23

DISCUSSION: 26

3D Reconstruction Utilizing SBF/SEM: 27

Functional Consequences of Anatomical and Morphological Features of Axon Terminals in GABAergic and Glutamatergic Systems: 28

Changes in the Number and Size of GABAergic Pallidothalamic Synapses in Parkinsonian Monkeys: Potential Functional Significance: 30

Differences in Ultrastructural Features of Pallidothalamic Terminals in the VApc and CM of Normal and Parkinsonian Monkeys: Potential Functional Implications: 32

Potential Consequences of Neuronal Degeneration on the Synaptic Innervation of CM: 33

Future Directions: 34

REFERENCES: 38

 List of Figures and Tables

Figure 1. Activity in the basal ganglia-thalamocortical loop in the normal and parkinsonian state: 2

Figure 2. Classification of terminal subtypes in the VApc and CM of control and MPTP-treated monkeys: 14

Figure 3. Pallidothalamic terminals forming multiple synapses with a large dendrite in the VApc of a control animal: 16

Figure 4. Pallidothalamic terminals in contact with a large dendrite in the VApc of an MPTP-treated monkey: 17

Figure 5. Quantification of ultrastructural features of pallidothalamic terminals in the VApc of a control and MPTP-treated monkey: 18

Figure 6. Pallidothalamic terminals forming synapses with a dendrite in the CM of a control and MPTP-treated monkey: 20

Figure 7. Quantification of ultrastructural features of pallidothalamic terminals in the CM of control and MPTP-treated monkeys: 21

Table 1. Postsynaptic target distribution of GPi terminals in the VApc (top) and CM (bottom) of a control and MPTP-treated monkey: 22

Figure 8. Comparison of ultrastructural features of pallidothalamic terminals between the VApc and CM of control monkeys: 24

Figure 9. Comparison of ultrastructural features of pallidothalamic terminals between the VApc and CM of MPTP-treated monkeys: 25

Figure 10. Comparison of 3D-Reconstructed Synapses in the VApc and CM of control and MPTP-treated monkeys: 26

 

 

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Ultrastructural Plasticity of Pallidothalamic GABAergic Terminals in Parkinson’s Disease: A 3D Electron Microscopy Study in the Parvocellular Ventral Anterior and Centromedian Thalamic Nuclei in MPTP-Treated Parkinsonian Monkeys () 2019-04-02 21:21:32 -0400

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