title: High-frequency stimulation of the globus pallidus interna nucleus modulates GFRα1 gene expression in the basal ganglia.
abstract: Deep brain stimulation (DBS) is an established therapy for movement disorders such as Parkinson's disease (PD). Although the efficacy of DBS is clear, its precise molecular mechanism remains unknown. The glial cell line derived factor (GDNF) family of ligands has been shown to confer neuroprotective effects on dopaminergic neurons, and putaminal infusion of GDNF have been investigated in PD patients with promising results. Despite the potential therapeutic role of GDNF in alleviating motor symptoms, there is no data on the effects of electrical stimulation on GDNF-family receptor (GFR) expression in the basal ganglia structures. Here, we report the effects of electrical stimulation on GFRα1 isoforms, particularly GFRα1a and GFRα1b. Wistar rats underwent 2 hours of high frequency stimulation (HFS) at the globus pallidus interna nucleus. A control group was subjected to a similar procedure but without stimulation. The HFS group, sacrificed 24 hours after treatment, had a threefold decrease in mRNA expression level of GFRα1b (p=0.037), but the expression level reverted to normal 72 hours after stimulation. Our preliminary data reveal the acute effects of HFS on splice isoforms of GFRα1, and suggest that HFS may modulate the splice isoforms of GFRα1a and GFRα1b to varying degrees. Going forward, elucidating the interactions between HFS and GFR may shed new insights into the complexity of GDNF signaling in the nervous system and lead to better design of clinical trials using these signaling pathways to halt disease progression in PD and other neurodegenerative diseases.
authors.affiliation: Department of Neurosurgery, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore. Electronic address: duncun_xk_ho@nni.com.sg.
authors.forename: Duncun Xun Kiat
authors.initials: DX
authors.lastname: Ho
authors.affiliation: Department of Neurosurgery, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore.
authors.forename: Yong Chee
authors.initials: YC
authors.lastname: Tan
authors.affiliation: Department of Neurosurgery, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore.
authors.forename: Jiayi
authors.initials: J
authors.lastname: Tan
authors.affiliation: Department of Biochemistry, National University of Singapore, Singapore.
authors.forename: Heng Phon
authors.initials: HP
authors.lastname: Too
authors.affiliation: Department of Neurosurgery, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore; Duke-NUS Graduate Medical School, Singapore. Electronic address: wai_hoe_ng@nni.com.sg.
authors.forename: Wai Hoe
authors.initials: WH
authors.lastname: Ng
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001479:Basal Ganglia / Q000502:physiology*; D046690:Deep Brain Stimulation; D015870:Gene Expression / Q000502:physiology; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000378:metabolism*; D005917:Globus Pallidus / Q000502:physiology*; D008297:Male; D059368:RNA Isoforms / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: C494989:Gfra1 protein, rat; C494992:Gfra2 protein, rat; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D059368:RNA Isoforms; D012333:RNA, Messenger
keywords: Deep brain stimulation; Electrical stimulation; GDNF-family receptor-α1; GFRα1b; Glial cell line-derived neurotrophic factor; High-frequency stimulation