Structural Plasticity of GABAergic Pallidothalamic Terminals in MPTP-Treated Parkinsonian Monkeys: A 3D Electron Microscopic Analysis

Overview

Journal eNeuro

Specialty Neurology

Date 2024 Mar 21

PMID 38514185

Authors

G J Masilamoni

H Kelly

A J Swain

J F Pare

R M Villalba

Y Smith

Affiliations

Soon will be listed here.

Abstract

The internal globus pallidus (GPi) is a major source of tonic GABAergic inhibition to the motor thalamus. In parkinsonism, the firing rate of GPi neurons is increased, and their pattern switches from a tonic to a burst mode, two pathophysiological changes associated with increased GABAergic pallidothalamic activity. In this study, we used high-resolution 3D electron microscopy to demonstrate that GPi terminals in the parvocellular ventral anterior nucleus (VApc) and the centromedian nucleus (CM), the two main GPi-recipient motor thalamic nuclei in monkeys, undergo significant morphometric changes in parkinsonian monkeys including (1) increased terminal volume in both nuclei; (2) increased surface area of synapses in both nuclei; (3) increased number of synapses/GPi terminals in the CM, but not VApc; and (4) increased total volume, but not number, of mitochondria/terminals in both nuclei. In contrast to GPi terminals, the ultrastructure of putative GABAergic nonpallidal terminals was not affected. Our results also revealed striking morphological differences in terminal volume, number/area of synapses, and volume/number of mitochondria between GPi terminals in VApc and CM of control monkeys. In conclusion, GABAergic pallidothalamic terminals are endowed with a high level of structural plasticity that may contribute to the development and maintenance of the abnormal increase in pallidal GABAergic outflow to the thalamus in the parkinsonian state. Furthermore, the evidence for ultrastructural differences between GPi terminals in VApc and CM suggests that morphologically distinct pallidothalamic terminals from single pallidal neurons may underlie specific physiological properties of pallidal inputs to VApc and CM in normal and diseased states.

References

Magnin M, Morel A, Jeanmonod D . Single-unit analysis of the pallidum, thalamus and subthalamic nucleus in parkinsonian patients. Neuroscience. 2000; 96(3):549-64. DOI: 10.1016/s0306-4522(99)00583-7. View

Mizukawa K, Sora Y, Ogawa N . Ultrastructural changes of the substantia nigra, ventral tegmental area and striatum in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Res Commun Chem Pathol Pharmacol. 1990; 67(3):307-20. View

Liu H, Ho P, Leung C, Pang S, Chang E, Choi Z . Aberrant mitochondrial morphology and function associated with impaired mitophagy and DNM1L-MAPK/ERK signaling are found in aged mutant Parkinsonian LRRK2 mice. Autophagy. 2020; 17(10):3196-3220. PMC: 8526027. DOI: 10.1080/15548627.2020.1850008. View

Brustovetsky T, Khanna R, Brustovetsky N . Involvement of CRMP2 in Regulation of Mitochondrial Morphology and Motility in Huntington's Disease. Cells. 2021; 10(11). PMC: 8619197. DOI: 10.3390/cells10113172. View

Vincent A, White K, Davey T, Philips J, Ogden R, Lawless C . Quantitative 3D Mapping of the Human Skeletal Muscle Mitochondrial Network. Cell Rep. 2019; 26(4):996-1009.e4. PMC: 6513570. DOI: 10.1016/j.celrep.2019.01.010. View

Masilamoni G, Bogenpohl J, Alagille D, Delevich K, Tamagnan G, Votaw J . Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys. Brain. 2011; 134(Pt 7):2057-73. PMC: 3122374. DOI: 10.1093/brain/awr137. View

Kultas-Ilinsky K, Ilinsky I . Fine structure of the magnocellular subdivision of the ventral anterior thalamic nucleus (VAmc) of Macaca mulatta: II. Organization of nigrothalamic afferents as revealed with EM autoradiography. J Comp Neurol. 1990; 294(3):479-89. DOI: 10.1002/cne.902940314. View

Hahn P, Russo G, Hashimoto T, Miocinovic S, Xu W, McIntyre C . Pallidal burst activity during therapeutic deep brain stimulation. Exp Neurol. 2008; 211(1):243-51. PMC: 2431132. DOI: 10.1016/j.expneurol.2008.01.032. View

Albin R, Young A, Penney J . The functional anatomy of basal ganglia disorders. Trends Neurosci. 1989; 12(10):366-75. DOI: 10.1016/0166-2236(89)90074-x. View

10.

Samaranch L, Blits B, San Sebastian W, Hadaczek P, Bringas J, Sudhakar V . MR-guided parenchymal delivery of adeno-associated viral vector serotype 5 in non-human primate brain. Gene Ther. 2017; 24(4):253-261. PMC: 5404203. DOI: 10.1038/gt.2017.14. View

11.

Duchen M . Mitochondria and Ca(2+)in cell physiology and pathophysiology. Cell Calcium. 2000; 28(5-6):339-48. DOI: 10.1054/ceca.2000.0170. View

12.

Shepherd G, Harris K . Three-dimensional structure and composition of CA3-->CA1 axons in rat hippocampal slices: implications for presynaptic connectivity and compartmentalization. J Neurosci. 1998; 18(20):8300-10. PMC: 6792846. View

13.

Favuzzi E, Rico B . Molecular diversity underlying cortical excitatory and inhibitory synapse development. Curr Opin Neurobiol. 2018; 53:8-15. DOI: 10.1016/j.conb.2018.03.011. View

14.

Soares J, Kliem M, Betarbet R, Greenamyre J, Yamamoto B, Wichmann T . Role of external pallidal segment in primate parkinsonism: comparison of the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism and lesions of the external pallidal segment. J Neurosci. 2004; 24(29):6417-26. PMC: 6729864. DOI: 10.1523/JNEUROSCI.0836-04.2004. View

15.

Telgkamp P, Padgett D, Ledoux V, Woolley C, Raman I . Maintenance of high-frequency transmission at purkinje to cerebellar nuclear synapses by spillover from boutons with multiple release sites. Neuron. 2004; 41(1):113-26. DOI: 10.1016/s0896-6273(03)00802-x. View

16.

Nicholls D, Budd S . Mitochondria and neuronal survival. Physiol Rev. 2000; 80(1):315-60. DOI: 10.1152/physrev.2000.80.1.315. View

17.

Wanaverbecq N, Bodor A, Bokor H, Slezia A, Luthi A, Acsady L . Contrasting the functional properties of GABAergic axon terminals with single and multiple synapses in the thalamus. J Neurosci. 2008; 28(46):11848-61. PMC: 6671651. DOI: 10.1523/JNEUROSCI.3183-08.2008. View

18.

Dharmadhikari S, Ma R, Yeh C, Stock A, Snyder S, Zauber S . Striatal and thalamic GABA level concentrations play differential roles for the modulation of response selection processes by proprioceptive information. Neuroimage. 2015; 120:36-42. PMC: 4589476. DOI: 10.1016/j.neuroimage.2015.06.066. View

19.

Ivannikov M, Sugimori M, Llinas R . Synaptic vesicle exocytosis in hippocampal synaptosomes correlates directly with total mitochondrial volume. J Mol Neurosci. 2012; 49(1):223-30. PMC: 3488359. DOI: 10.1007/s12031-012-9848-8. View

20.

Matz J, Gilyan A, Kolar A, McCarvill T, Krueger S . Rapid structural alterations of the active zone lead to sustained changes in neurotransmitter release. Proc Natl Acad Sci U S A. 2010; 107(19):8836-41. PMC: 2889309. DOI: 10.1073/pnas.0906087107. View