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Subthalamic Nucleus Deep Brain Stimulation Does Not Modify the Functional Deficits or Axonopathy Induced by Nigrostriatal α-Synuclein Overexpression.
Sci Rep. 2017 11 27; 7(1):16356.SR

Abstract

Subthalamic nucleus deep brain stimulation (STN DBS) protects dopaminergic neurons of the substantia nigra pars compacta (SNpc) against 6-OHDA and MPTP. We evaluated STN DBS in a parkinsonian model that displays α-synuclein pathology using unilateral, intranigral injections of recombinant adeno-associated virus pseudotype 2/5 to overexpress wildtype human α-synuclein (rAAV2/5 α-syn). A low titer of rAAV2/5 α-syn results in progressive forelimb asymmetry, loss of striatal dopaminergic terminal density and modest loss of SNpc dopamine neurons after eight weeks, corresponding to robust human-Snca expression and no effect on rat-Snca, Th, Bdnf or Trk2. α-syn overexpression increased phosphorylation of ribosomal protein S6 (p-rpS6) in SNpc neurons, a readout of trkB activation. Rats received intranigral injections of rAAV2/5 α-syn and three weeks later received four weeks of STN DBS or electrode implantation that remained inactive. STN DBS did not protect against α-syn-mediated deficits in forelimb akinesia, striatal denervation or loss of SNpc neuron, nor did STN DBS elevate p-rpS6 levels further. ON stimulation, forelimb asymmetry was exacerbated, indicating α-syn overexpression-mediated neurotransmission deficits. These results demonstrate that STN DBS does not protect the nigrostriatal system against α-syn overexpression-mediated toxicity. Whether STN DBS can be protective in other models of synucleinopathy is unknown.

Authors+Show Affiliations

Department of Translational Science & Molecular Medicine, Michigan State University, Grand Rapids, MI, USA. MD/PhD Program, Michigan State University, Grand Rapids, MI, USA. Neuroscience Graduate Training Program, Michigan State University, Grand Rapids, MI, USA.Department of Translational Science & Molecular Medicine, Michigan State University, Grand Rapids, MI, USA. Mercy Health Saint Mary's, Grand Rapids, MI, USA.Department of Translational Science & Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.Department of Translational Science & Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.Department of Translational Science & Molecular Medicine, Michigan State University, Grand Rapids, MI, USA. Mercy Health Saint Mary's, Grand Rapids, MI, USA.Department of Translational Science & Molecular Medicine, Michigan State University, Grand Rapids, MI, USA. Neuroscience Graduate Training Program, Michigan State University, Grand Rapids, MI, USA.Department of Translational Science & Molecular Medicine, Michigan State University, Grand Rapids, MI, USA. Neuroscience Graduate Training Program, Michigan State University, Grand Rapids, MI, USA.Department of Translational Science & Molecular Medicine, Michigan State University, Grand Rapids, MI, USA. Mercy Health Saint Mary's, Grand Rapids, MI, USA.Department of Translational Science & Molecular Medicine, Michigan State University, Grand Rapids, MI, USA. Mercy Health Saint Mary's, Grand Rapids, MI, USA.Department of Translational Science & Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.Department of Translational Science & Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.Department of Translational Science & Molecular Medicine, Michigan State University, Grand Rapids, MI, USA. caryl.sortwell@hc.msu.edu. Mercy Health Saint Mary's, Grand Rapids, MI, USA. caryl.sortwell@hc.msu.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29180681

Citation

Fischer, D Luke, et al. "Subthalamic Nucleus Deep Brain Stimulation Does Not Modify the Functional Deficits or Axonopathy Induced By Nigrostriatal α-Synuclein Overexpression." Scientific Reports, vol. 7, no. 1, 2017, p. 16356.
Fischer DL, Manfredsson FP, Kemp CJ, et al. Subthalamic Nucleus Deep Brain Stimulation Does Not Modify the Functional Deficits or Axonopathy Induced by Nigrostriatal α-Synuclein Overexpression. Sci Rep. 2017;7(1):16356.
Fischer, D. L., Manfredsson, F. P., Kemp, C. J., Cole-Strauss, A., Lipton, J. W., Duffy, M. F., Polinski, N. K., Steece-Collier, K., Collier, T. J., Gombash, S. E., Buhlinger, D. J., & Sortwell, C. E. (2017). Subthalamic Nucleus Deep Brain Stimulation Does Not Modify the Functional Deficits or Axonopathy Induced by Nigrostriatal α-Synuclein Overexpression. Scientific Reports, 7(1), 16356. https://doi.org/10.1038/s41598-017-16690-x
Fischer DL, et al. Subthalamic Nucleus Deep Brain Stimulation Does Not Modify the Functional Deficits or Axonopathy Induced By Nigrostriatal α-Synuclein Overexpression. Sci Rep. 2017 11 27;7(1):16356. PubMed PMID: 29180681.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Subthalamic Nucleus Deep Brain Stimulation Does Not Modify the Functional Deficits or Axonopathy Induced by Nigrostriatal α-Synuclein Overexpression. AU - Fischer,D Luke, AU - Manfredsson,Fredric P, AU - Kemp,Christopher J, AU - Cole-Strauss,Allyson, AU - Lipton,Jack W, AU - Duffy,Megan F, AU - Polinski,Nicole K, AU - Steece-Collier,Kathy, AU - Collier,Timothy J, AU - Gombash,Sara E, AU - Buhlinger,Daniel J, AU - Sortwell,Caryl E, Y1 - 2017/11/27/ PY - 2017/03/07/received PY - 2017/11/16/accepted PY - 2017/11/29/entrez PY - 2017/11/29/pubmed PY - 2019/7/13/medline SP - 16356 EP - 16356 JF - Scientific reports JO - Sci Rep VL - 7 IS - 1 N2 - Subthalamic nucleus deep brain stimulation (STN DBS) protects dopaminergic neurons of the substantia nigra pars compacta (SNpc) against 6-OHDA and MPTP. We evaluated STN DBS in a parkinsonian model that displays α-synuclein pathology using unilateral, intranigral injections of recombinant adeno-associated virus pseudotype 2/5 to overexpress wildtype human α-synuclein (rAAV2/5 α-syn). A low titer of rAAV2/5 α-syn results in progressive forelimb asymmetry, loss of striatal dopaminergic terminal density and modest loss of SNpc dopamine neurons after eight weeks, corresponding to robust human-Snca expression and no effect on rat-Snca, Th, Bdnf or Trk2. α-syn overexpression increased phosphorylation of ribosomal protein S6 (p-rpS6) in SNpc neurons, a readout of trkB activation. Rats received intranigral injections of rAAV2/5 α-syn and three weeks later received four weeks of STN DBS or electrode implantation that remained inactive. STN DBS did not protect against α-syn-mediated deficits in forelimb akinesia, striatal denervation or loss of SNpc neuron, nor did STN DBS elevate p-rpS6 levels further. ON stimulation, forelimb asymmetry was exacerbated, indicating α-syn overexpression-mediated neurotransmission deficits. These results demonstrate that STN DBS does not protect the nigrostriatal system against α-syn overexpression-mediated toxicity. Whether STN DBS can be protective in other models of synucleinopathy is unknown. SN - 2045-2322 UR - https://www.unboundmedicine.com/medline/citation/29180681/Subthalamic_Nucleus_Deep_Brain_Stimulation_Does_Not_Modify_the_Functional_Deficits_or_Axonopathy_Induced_by_Nigrostriatal_α_Synuclein_Overexpression_ L2 - https://doi.org/10.1038/s41598-017-16690-x DB - PRIME DP - Unbound Medicine ER -