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Optogenetic Inactivation of the Subthalamic Nucleus Improves Forelimb Akinesia in a Rat Model of Parkinson Disease

Yoon, Hyung Ho MS*,‡; Park, Jin Hoon MD, PhD§,*; Kim, Yong Hwan BS; Min, Joongkee PhD; Hwang, Eunmi PhD; Lee, C. Justin PhD; Francis Suh, Jun-Kyo PhD#; Hwang, Onyou PhD**; Jeon, Sang Ryong MD, PhD

doi: 10.1227/NEU.0000000000000297

BACKGROUND: The inhibition of neuronal activity by electrical deep brain stimulation is one of the mechanisms explaining the therapeutic effects in patients with Parkinson disease (PD) but cannot specifically activate or inactivate different types of neurons. Recently, a new technology based on optogenetics has been developed to modulate the activity of specific neurons. However, the therapeutic effects of optical inactivation in the subthalamic nucleus (STN) have not been fully investigated.

OBJECTIVE: To perform various behavioral tests to evaluate changes in motor functions in a PD rat model after optogene expression and, unlike previous studies, to assess the therapeutic effects of direct optogenetic inactivation in the STN.

METHODS: 6-Hydroxydopamine-induced hemiparkinsonian rats received injections of hSynapsin1-NpHR-YFP adeno-associated virus or an equivalent volume of phosphate-buffered saline. Three weeks after injection of adeno-associated virus or phosphate-buffered saline, the optic fiber was implanted into the ipsilateral STN. A stepping test, a cylinder test, and an apomorphine-induced rotation test were performed in 3 sequential steps: during light-off state, during light stimulation, and again during light-off state.

RESULTS: Stepping tests revealed that optical inhibition of the STN significantly improved 6-hydroxydopamine-induced forelimb akinesia. PD motor signs, as assessed by cylinder and apomorphine tests, were not affected by optical inhibition. Immunofluorescence revealed that halorhodopsin was highly expressed and colocalized with vesicular glutamate transporter 2 in the STN.

CONCLUSION: Optogenetic inhibition in the STN may be effective in improving contralateral forelimb akinesia but not in changing forelimb preference or reducing dopaminergic receptor supersensitivity. These findings are useful as a basis for future studies on optogenetics in PD.

Abbreviations: AAV, adeno-associated virus

DBS, deep brain stimulation

PBS, phosphate-buffered saline

PD, Parkinson disease

6-OHDA, 6-hydroxydopamine

SN, substantia nigra

STN, subthalamic nucleus

TH, tyrosine hydroxylase

VGLUT2, vesicular glutamate transporter 2

Department of Neurological Surgery and

**Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Republic of Korea;

§Department of Neurological Surgery, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Republic of Korea;

Department of Computer Science and Engineering, Bioengineering Graduate Program, University of Notre Dame, Notre Dame, Indiana;

Center for Neural Science and WCI Center for Functional Connectomics, Korea Institute of Science and Technology, Seoul, Republic of Korea;

#Center for Bionics of Korea Institute of Science and Technology, Seoul, Republic of Korea

Correspondence: Sang Ryong Jeon, MD, PhD, Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Pungnap-2 dong, Songpa-gu, Seoul 138-736, Korea. E-mail:

* These authors contributed equally to this work.

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Received October 14, 2013

Accepted January 14, 2014

Copyright © by the Congress of Neurological Surgeons