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Selective elimination of glutamatergic synapses on striatopallidal neurons in Parkinson disease models

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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Figure 1: The long splice variant of the Cav1.3α1 subunit is localized in spines of striatal MSNs.
Figure 2: Genetic deletion of Cav1.3α1 subunits increases the number of spines and the frequency of spontaneous glutamatergic synaptic events.
Figure 3: Dopamine depletion causes a reduction in spine density in the D2 receptor–expressing (but not D1 receptor–expressing) MSNs.
Figure 4: Immunoelectron microscopic study of spines and synapses in the intact and dopamine-denervated striatum.
Figure 5: Dopamine-dependent elimination of spines on D2 receptor–expressing striatopallidal MSNs requires Cav1.3 channel activation.

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References

  1. Albin, R.L., Young, A.B. & Penney, J.B. The functional anatomy of basal ganglia disorders. Trends Neurosci. 12, 366–375 (1989).

    Article  CAS  Google Scholar 

  2. Gerfen, C.R. et al. D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science 250, 1429–1432 (1990).

    Article  CAS  Google Scholar 

  3. Surmeier, D.J., Song, W.J. & Yan, Z. Coordinated expression of dopamine receptors in neostriatal MSNs. J. Neurosci. 16, 6579–6591 (1996).

    Article  CAS  Google Scholar 

  4. Bolam, J.P., Hanley, J.J., Booth, P.A. & Bevan, M.D. Synaptic organisation of the basal ganglia. J. Anat. 196, 527–542 (2000).

    Article  CAS  Google Scholar 

  5. Raz, A., Vaadia, E. & Bergman, H. Firing patterns and correlations of spontaneous discharge of pallidal neurons in the normal and the tremulous 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine vervet model of parkinsonism. J. Neurosci. 20, 8559–8571 (2000).

    Article  CAS  Google Scholar 

  6. Wichmann, T. & DeLong, M.R. Functional neuroanatomy of the basal ganglia in Parkinson's disease. Adv. Neurol. 91, 9–18 (2003).

    PubMed  Google Scholar 

  7. Terman, D., Rubin, J.E., Yew, A.C. & Wilson, C.J. Activity patterns in a model for the subthalamopallidal network of the basal ganglia. J. Neurosci. 22, 2963–2976 (2002).

    Article  CAS  Google Scholar 

  8. Tseng, K.Y., Kasanetz, F., Kargieman, L., Riquelme, L.A. & Murer, M.G. Cortical slow oscillatory activity is reflected in the membrane potential and spike trains of striatal neurons in rats with chronic nigrostriatal lesions. J. Neurosci. 21, 6430–6439 (2001).

    Article  CAS  Google Scholar 

  9. Nisenbaum, E.S., Stricker, E.M., Zigmond, M.J. & Berger, T.W. Long-term effects of dopamine-depleting brain lesions on spontaneous activity of type II striatal neurons: relation to behavioral recovery. Brain Res. 398, 221–230 (1986).

    Article  CAS  Google Scholar 

  10. Ingham, C.A., Hood, S.H., Taggart, P. & Arbuthnott, G.W. Plasticity of synapses in the rat neostriatum after unilateral lesion of the nigrostriatal dopaminergic pathway. J. Neurosci. 18, 4732–4743 (1998).

    Article  CAS  Google Scholar 

  11. Picconi, B. et al. Loss of bidirectional striatal synaptic plasticity in L-DOPA-induced dyskinesia. Nat. Neurosci. 6, 501–506 (2003).

    Article  CAS  Google Scholar 

  12. Dunah, A.W. et al. Alterations in subunit expression, composition, and phosphorylation of striatal N-methyl-D-aspartate glutamate receptors in a rat 6-hydroxydopamine model of Parkinson's disease. Mol. Pharmacol. 57, 342–352 (2000).

    CAS  PubMed  Google Scholar 

  13. Gubellini, P. et al. Experimental parkinsonism alters endocannabinoid degradation: implications for striatal glutamatergic transmission. J. Neurosci. 22, 6900–6907 (2002).

    Article  CAS  Google Scholar 

  14. Pang, Z., Ling, G.Y., Gajendiran, M. & Xu, Z.C. Enhanced excitatory synaptic transmission in spiny neurons of rat striatum after unilateral dopamine denervation. Neurosci. Lett. 308, 201–205 (2001).

    Article  CAS  Google Scholar 

  15. Heintz, N. BAC to the future: the use of bac transgenic mice for neuroscience research. Nat. Rev. Neurosci. 2, 861–870 (2001).

    Article  CAS  Google Scholar 

  16. Mermelstein, P.G., Bito, H., Deisseroth, K. & Tsien, R.W. Critical dependence of cAMP response element-binding protein phosphorylation on L-type calcium channels supports a selective response to EPSPs in preference to action potentials. J. Neurosci. 20, 266–273 (2000).

    Article  CAS  Google Scholar 

  17. Dolmetsch, R.E., Pajvani, U., Fife, K., Spotts, J.M. & Greenberg, M.E. Signaling to the nucleus by an L-type calcium channel-calmodulin complex through the MAP kinase pathway. Science 294, 333–339 (2001).

    Article  CAS  Google Scholar 

  18. Rajadhyaksha, A. et al. L-Type Ca(2+) channels are essential for glutamate-mediated CREB phosphorylation and c-fos gene expression in striatal neurons. J. Neurosci. 19, 6348–6359 (1999).

    Article  CAS  Google Scholar 

  19. Lovinger, D.M., Partridge, J.G. & Tang, K.C. Plastic control of striatal glutamatergic transmission by ensemble actions of several neurotransmitters and targets for drugs of abuse. Ann. NY Acad. Sci. 1003, 226–240 (2003).

    Article  CAS  Google Scholar 

  20. Hernandez-Lopez, S. et al. D2 dopamine receptors in striatal medium spiny neurons reduce L-type Ca2+ currents and excitability via a novel PLC[beta]1–IP3-calcineurin-signaling cascade. J. Neurosci. 20, 8987–8995 (2000).

    Article  CAS  Google Scholar 

  21. Surmeier, D.J., Bargas, J., Hemmings, H.C. Jr., Nairn, A.C. & Greengard, P. Modulation of calcium currents by a D1 dopaminergic protein kinase/phosphatase cascade in rat neostriatal neurons. Neuron 14, 385–397 (1995).

    Article  CAS  Google Scholar 

  22. Olson, P.A. et al. G-protein-coupled receptor modulation of striatal CaV1.3 L-type Ca2+ channels is dependent on a Shank-binding domain. J. Neurosci. 25, 1050–1062 (2005).

    Article  CAS  Google Scholar 

  23. Xu, W. & Lipscombe, D. Neuronal Ca(V)1.3alpha(1) L-type channels activate at relatively hyperpolarized membrane potentials and are incompletely inhibited by dihydropyridines. J. Neurosci. 21, 5944–5951 (2001).

    Article  CAS  Google Scholar 

  24. Zhang, H. et al. Association of CaV1.3 L-type calcium channels with Shank. J. Neurosci. 25, 1037–1049 (2005).

    Article  CAS  Google Scholar 

  25. Calabresi, P. et al. Synaptic transmission in the striatum: from plasticity to neurodegeneration. Prog. Neurobiol. 61, 231–265 (2000).

    Article  CAS  Google Scholar 

  26. Platzer, J. et al. Congenital deafness and sinoatrial node dysfunction in mice lacking class D L-type Ca2+ channels. Cell 102, 89–97 (2000).

    Article  CAS  Google Scholar 

  27. Wilson, C.J. Understanding the neostriatal microcircuitry: high-voltage electron microscopy. Microsc. Res. Tech. 29, 368–380 (1994).

    Article  CAS  Google Scholar 

  28. LaHoste, G.J., Yu, J. & Marshall, J.F. Striatal Fos expression is indicative of dopamine D1/D2 synergism and receptor supersensitivity. Proc. Natl. Acad. Sci. USA 90, 7451–7455 (1993).

    Article  CAS  Google Scholar 

  29. Ingham, C.A., Hood, S.H., van Maldegem, B., Weenink, A. & Arbuthnott, G.W. Morphological changes in the rat neostriatum after unilateral 6-hydroxydopamine injections into the nigrostriatal pathway. Exp. Brain Res. 93, 17–27 (1993).

    Article  CAS  Google Scholar 

  30. McNeill, T.H., Brown, S.A., Rafols, J.A. & Shoulson, I. Atrophy of medium spiny I striatal dendrites in advanced Parkinson's disease. Brain Res. 455, 148–152 (1988).

    Article  CAS  Google Scholar 

  31. Stephens, B. et al. Evidence of a breakdown of corticostriatal connections in Parkinson's disease. Neuroscience 132, 741–754 (2005).

    Article  CAS  Google Scholar 

  32. Carter, A.G. & Sabatini, B.L. State-dependent calcium signaling in dendritic spines of striatal medium spiny neurons. Neuron 44, 483–493 (2004).

    Article  CAS  Google Scholar 

  33. Tsien, J.Z. Linking Hebb's coincidence-detection to memory formation. Curr. Opin. Neurobiol. 10, 266–273 (2000).

    Article  CAS  Google Scholar 

  34. Nagerl, U.V., Eberhorn, N., Cambridge, S.B. & Bonhoeffer, T. Bidirectional activity-dependent morphological plasticity in hippocampal neurons. Neuron 44, 759–767 (2004).

    Article  Google Scholar 

  35. Zhou, Q., Homma, K.J. & Poo, M.M. Shrinkage of dendritic spines associated with long-term depression of hippocampal synapses. Neuron 44, 749–757 (2004).

    Article  CAS  Google Scholar 

  36. Segal, M. Rapid plasticity of dendritic spine: hints to possible functions? Prog. Neurobiol. 63, 61–70 (2001).

    Article  CAS  Google Scholar 

  37. Oertner, T.G. & Matus, A. Calcium regulation of actin dynamics in dendritic spines. Cell Calcium 37, 477–482 (2005).

    Article  CAS  Google Scholar 

  38. Wilson, C.J. & Kawaguchi, Y. The origins of two-state spontaneous membrane potential fluctuations of neostriatal spiny neurons. J. Neurosci. 16, 2397–2410 (1996).

    Article  CAS  Google Scholar 

  39. Galarraga, E., Bargas, J., Martinez-Fong, D. & Aceves, J. Spontaneous synaptic potentials in dopamine-denervated neostriatal neurons. Neurosci. Lett. 81, 351–355 (1987).

    Article  CAS  Google Scholar 

  40. Picconi, B., Centonze, D., Rossi, S., Bernardi, G. & Calabresi, P. Therapeutic doses of L-dopa reverse hypersensitivity of corticostriatal D2-dopamine receptors and glutamatergic overactivity in experimental parkinsonism. Brain 127, 1661–1669 (2004).

    Article  Google Scholar 

  41. Cepeda, C. et al. Facilitated glutamatergic transmission in the striatum of D2 dopamine receptor-deficient mice. J. Neurophysiol. 85, 659–670 (2001).

    Article  CAS  Google Scholar 

  42. Bamford, N.S. et al. Heterosynaptic dopamine neurotransmission selects sets of corticostriatal terminals. Neuron 42, 653–663 (2004).

    Article  CAS  Google Scholar 

  43. Turrigiano, G.G. Homeostatic plasticity in neuronal networks: the more things change, the more they stay the same. Trends Neurosci. 22, 221–227 (1999).

    Article  CAS  Google Scholar 

  44. Baik, J.H. et al. Parkinsonian-like locomotor impairment in mice lacking dopamine D2 receptors. Nature 377, 424–428 (1995).

    Article  CAS  Google Scholar 

  45. Gross, C.E., Boraud, T., Guehl, D., Bioulac, B. & Bezard, E. From experimentation to the surgical treatment of Parkinson's disease: prelude or suite in basal ganglia research? Prog. Neurobiol. 59, 509–532 (1999).

    Article  CAS  Google Scholar 

  46. Hutchison, W.D. et al. Neuronal oscillations in the basal ganglia and movement disorders: evidence from whole animal and human recordings. J. Neurosci. 24, 9240–9243 (2004).

    Article  CAS  Google Scholar 

  47. Day, M. et al. Dendritic excitability of mouse frontal cortex pyramidal neurons is shaped by the interaction among HCN, Kir2, and Kleak channels. J. Neurosci. 25, 8776–8787 (2005).

    Article  CAS  Google Scholar 

  48. Tkatch, T., Baranauskas, G. & Surmeier, D.J. Basal forebrain neurons adjacent to the globus pallidus co-express GABAergic and cholinergic marker mRNAs. Neuroreport 9, 1935–1939 (1998).

    Article  CAS  Google Scholar 

  49. Scholl, D.A. Dendritic organization in the neurons of the visual and motor cortices of the cat. J. Anat. 87, 387–406 (1953).

    Google Scholar 

  50. Levey, A.I. et al. Localization of D1 and D2 dopamine receptors in brain with subtype-specific antibodies. Proc. Natl. Acad. Sci. USA 90, 8861–8865 (1993).

    Article  CAS  Google Scholar 

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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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Correspondence to D James Surmeier.

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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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