PT  - JOURNAL ARTICLE
AU  - D. Luke Fischer
AU  - Christopher J. Kemp
AU  - Allyson Cole-Strauss
AU  - Nicole K. Polinski
AU  - Katrina L. Paumier
AU  - Jack W. Lipton
AU  - Kathy Steece-Collier
AU  - Timothy J. Collier
AU  - Daniel J. Buhlinger
AU  - Caryl E. Sortwell
TI  - Subthalamic Nucleus Deep Brain Stimulation Employs trkB Signaling for Neuroprotection and Functional Restoration
AID  - 10.1523/JNEUROSCI.2060-16.2017
DP  - 2017 Jul 12
TA  - The Journal of Neuroscience
PG  - 6786--6796
VI  - 37
IP  - 28
4099  - http://www.jneurosci.org/content/37/28/6786.short
4100  - http://www.jneurosci.org/content/37/28/6786.full
SO  - J. Neurosci.2017 Jul 12; 37
AB  - Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is the most common neurosurgical treatment for Parkinson's disease motor symptoms. In preclinical models, STN DBS provides neuroprotection for substantia nigra (SN) dopamine neurons and increases BDNF in the nigrostriatal system and primary motor cortex. However, whether BDNF signaling in the SN participates in the neuroprotective effects of DBS remains unknown. We demonstrate that STN DBS in male rats activates signaling downstream of tropomyosin receptor kinase type B (trkB), namely, phosphorylation of Akt and ribosomal protein S6, in SN neurons. Long-term trkB blockade abolished STN DBS-mediated neuroprotection of SN neurons following progressive 6-hydroxydopamine lesion and was associated with decreased phosphorylated ribosomal protein S6 immunoreactivity. Acute trkB blockade in rats with stable nigrostriatal denervation attenuated the forelimb akinesia improvement normally induced by STN DBS. These results suggest that STN DBS increases BDNF-trkB signaling to contribute to the neuroprotective and symptomatic efficacy of STN DBS.SIGNIFICANCE STATEMENT Subthalamic nucleus deep brain stimulation (STN DBS) is increasingly used in mid- to late-stage Parkinson's disease (PD) but with an incomplete knowledge of its molecular mechanisms. STN DBS is neuroprotective against neurotoxicants in animal models and increases BDNF. This study is the first to show that BDNF signaling through the cognate tropomyosin receptor kinase type B (trkB) receptor occurs in substantia nigra pars compacta neurons and is required for neuroprotection. In addition, blockade of trkB unexpectedly reduced the functional benefit of STN DBS on a short timescale that is inconsistent with canonical trkB signaling pathways, suggesting a noncanonical role for trkB in STN DBS-mediated behavioral effects. Together, these data implicate trkB signaling in the symptomatic efficacy and disease-modifying potential of STN DBS.