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Subthalamic Nucleus Stimulation Increases Brain Derived Neurotrophic Factor in the Nigrostriatal System and Primary Motor Cortex

Article type: Research Article

Authors: Spieles-Engemann, Anne L.; | Steece-Collier, Kathy | Behbehani, Michael M. | Collier, Timothy J. | Wohlgenant, Susan L. | Kemp, Christopher J. | Cole-Strauss, Allyson | Levine, Nathan D. | Gombash, Sara E.; | Thompson, Valerie B.; | Lipton, Jack W. | Sortwell, Caryl E.

Affiliations: Department of Neurology, University of Cincinnati, Cincinnati, OH, USA | Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, OH, USA | Department of Psychiatry, University of Cincinnati, Cincinnati, OH, USA | Graduate Program in Neuroscience, University of Cincinnati, Cincinnati, OH, USA | Department of Translational Science and Molecular Medicine, Michigan State University and The Udall Center of Excellence in Parkinson's Disease Research, Michigan State University, Grand Rapids, MI, USA

Note: [] Correspondence to: Caryl E. Sortwell, Department of Translational Science and Molecular Medicine, Michigan State University and The Udall Center of Excellence in Parkinson's Disease Research, Michigan State University, Grand Rapids, MI 49503, USA. E-mail: [email protected]

Keywords: Deep brain stimulation, Parkinson's disease, basal ganglia, trophic factors

DOI: 10.3233/JPD-2011-11008

Journal: Journal of Parkinson's Disease, vol. 1, no. 1, pp. 123-136, 2011

Published: 2011
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Abstract

The mechanisms underlying the effects of long-term deep brain stimulation of the subthalamic nucleus (STN DBS) as a therapy for Parkinson's disease (PD) remain poorly understood. The present study examined whether functionally effective, long-term STN DBS modulates glial cell line-derived neurotrophic factor (GDNF) and/or brain-derived neurotrophic factor (BDNF) in both unlesioned and unilateral 6-hydroxydopamine lesioned rats. Lesioned rats that received two weeks of continuous unilateral STN DBS exhibited significant improvements in parkinsonian motor behaviors in tests of forelimb akinesia and rearing activity. Unilateral STN DBS did not increase GDNF in the nigrostriatal system, primary motor cortex (M1), or hippocampus of unlesioned rats. In contrast, unilateral STN DBS increased BDNF protein 2–3 fold bilaterally in the nigrostriatal system with the location (substantia nigra vs. striatum) dependent upon lesion status. Further, BDNF protein was bilaterally increased in M1 cortex by as much as 2 fold regardless of lesion status. STN DBS did not impact cortical regions that receive less input from the STN. STN DBS also was associated with bilateral increases in BDNF mRNA in the substantia nigra (SN) and internal globus pallidus (GPi). The increase observed in GPi was completely blocked by pretreatment with 5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801), suggesting that the activation of N-methyl-D-aspartate (NMDA) receptors was involved in this phenomenon. The upregulation of BDNF associated with long term STN DBS suggest that this therapy may exert pronounced and underappreciated effects on plasticity in the basal ganglia circuitry that may play a role in the symptomatic effects of this therapy as well as support the neuroprotective effect of stimulation documented in this rat model.

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