Striatal Afferent BDNF Is Disrupted by Synucleinopathy and Partially Restored by STN DBS.

Autor:	Miller KM; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, Michigan 49503.; Neuroscience Graduate Program, College of Natural Science, Michigan State University, East Lansing, Michigan 48824., Patterson JR; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, Michigan 49503., Kochmanski J; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, Michigan 49503., Kemp CJ; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, Michigan 49503., Stoll AC; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, Michigan 49503.; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan 48824., Onyekpe CU; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, Michigan 49503., Cole-Strauss A; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, Michigan 49503., Steece-Collier K; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, Michigan 49503.; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, Michigan 49503., Howe JW; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, Michigan 49503.; Neuroscience Graduate Program, College of Natural Science, Michigan State University, East Lansing, Michigan 48824., Luk KC; Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104., Sortwell CE; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, Michigan 49503 sortwell@msu.edu.; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, Michigan 49503.
Jazyk:	angličtina
Zdroj:	The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2021 Mar 03; Vol. 41 (9), pp. 2039-2052. Date of Electronic Publication: 2021 Jan 20.
DOI:	10.1523/JNEUROSCI.1952-20.2020
Abstrakt:	Preclinical studies show a link between subthalamic nucleus (STN) deep brain stimulation (DBS) and neuroprotection of nigrostriatal dopamine (DA) neurons, potentially through brain-derived neurotrophic factor (BDNF) signaling. However, the question of whether DBS of the STN can be disease-modifying in Parkinson's disease (PD) remains unanswered. In particular, the impact of STN DBS on α-synuclein (α-syn) aggregation, inclusion-associated neuroinflammation, and BDNF levels has yet to be examined in the context of synucleinopathy. To address this, we examined the effects of STN DBS on BDNF using the α-syn preformed fibril (PFF) model in male rats. While PFF injection resulted in accumulation of phosphorylated α-syn (pSyn) inclusions in the substantia nigra pars compacta (SNpc) and cortical areas, STN DBS did not impact PFF-induced accumulation of pSyn inclusions in the SNpc. In addition, nigral pSyn inclusions were associated with increased microgliosis and astrogliosis; however, the magnitude of these processes was not altered by STN DBS. Total BDNF protein was not impacted by pSyn inclusions, but the normally positive association of nigrostriatal and corticostriatal BDNF was reversed in rats with PFF-induced nigrostriatal and corticostriatal inclusions. Despite this, rats receiving both STN DBS and PFF injection showed increased BDNF protein in the striatum, which partially restored the normal corticostriatal relationship. Our results suggest that pathologic α-syn inclusions disrupt anterograde BDNF transport within nigrostriatal and corticostriatal circuitry. Further, STN DBS has the potential to exert protective effects by modifying the long-term neurodegenerative consequences of synucleinopathy. SIGNIFICANCE STATEMENT An increase in brain-derived neurotrophic factor (BDNF) has been linked to the neuroprotection elicited by subthalamic nucleus (STN) deep brain stimulation (DBS) in neurotoxicant models of Parkinson's disease (PD). However, whether STN DBS can similarly increase BDNF in nigrostriatal and corticostriatal circuitry in the presence of α-synuclein (α-syn) inclusions has not been examined. We examined the impact of STN DBS on rats in which accumulation of α-syn inclusions is induced by injection of α-syn preformed fibrils (PFFs). STN DBS significantly increased striatal BDNF protein in rats seeded with α-syn inclusions and partially restored the normal corticostriatal BDNF relationship. These findings suggest that STN DBS can drive BDNF in the parkinsonian brain and retains the potential for neuroprotection in PD. (Copyright © 2021 Miller et al.)
Databáze:	MEDLINE
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