Abstract
Parkinson disease is a common neurodegenerative disorder that leads to difficulty in effectively translating thought into action. Although it is known that dopaminergic neurons that innervate the striatum die in Parkinson disease, it is not clear how this loss leads to symptoms. Recent work has implicated striatopallidal medium spiny neurons (MSNs) in this process, but how and precisely why these neurons change is not clear. Using multiphoton imaging, we show that dopamine depletion leads to a rapid and profound loss of spines and glutamatergic synapses on striatopallidal MSNs but not on neighboring striatonigral MSNs. This loss of connectivity is triggered by a new mechanism—dysregulation of intraspine Cav1.3 L-type Ca2+ channels. The disconnection of striatopallidal neurons from motor command structures is likely to be a key step in the emergence of pathological activity that is responsible for symptoms in Parkinson disease.
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Acknowledgements
We thank P. Penzes, A. Contractor, M. Bevan, H. Kita and C. Wilson for their commentary on our work; T. Tkatch for designing the dopamine receptor primers used to characterize the BAC transgenics; A. Wright, P. Taggert and S. Hood for help with the synapse counts; I. Bezprozvanny for supplying Cav1.3α1 subunit antisera; and N. Heintz, P. Greengard and the National Institute of Neurological Disorders and Stroke Gene Expression Nervous System Atlas (NINDS GENSAT) program for supplying BAC transgenic mice. This work was funded by the US National Institutes of Health (grants NS 34696 and NS 047085 to D.J.S., NS 19608 to S.S. and NS 44282 to A.D.), the Picower Foundation (D.J.S.), the Wellcome Trust and the United Kingdom Parkinson Disease Society (G.W.A. and C.A.I.) and the National Parkinson Foundation Center of Excellence (A.D.).
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Supplementary information
Supplementary Fig. 1
Properties of mEPSCs recorded in striatonigral and striatopallidal neurons before and after reserpine treatment. (PDF 1080 kb)
Supplementary Fig. 2
Alterations in dendritic length and branching following dopamine depletion. (PDF 452 kb)
Supplementary Fig. 3
Light microscopic images of coronal sections through the rat brain showing the anterior mesencephalon and striatum in animals receiving a unilateral 6OHDA lesion. (PDF 21831 kb)
Supplementary Fig. 4
Serial electron micrographs of the rat striatum showing two sets of disector triplets from the control or 6-OHDA lesioned hemispheres. (PDF 14394 kb)
Supplementary Fig. 5
mEPSCs frequency increases following reserpine treatment when K+-based pipette solutions are used. (PDF 502 kb)
Supplementary Fig. 6
Properties of mEPSCs recorded in control striatonigral neurons and after reserpine treatment using recording conditions as described by Gubellini et al.15. (PDF 728 kb)
Supplementary Fig. 7
Properties of mEPSCs recorded in control striatopallidal neurons and after reserpine treatment using recording conditions as in Supplementary figure 6. (PDF 358 kb)
Supplementary Fig. 8
Schematic representation of the possible sequence of events leading to the elimination of synapses and spines in striatopallidal neurons following dopamine depletion. (PDF 217 kb)
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Day, M., Wang, Z., Ding, J. et al. Selective elimination of glutamatergic synapses on striatopallidal neurons in Parkinson disease models. Nat Neurosci 9, 251–259 (2006). https://doi.org/10.1038/nn1632
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DOI: https://doi.org/10.1038/nn1632
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