Objective: Study the potential of optogenetic suppression of STN neurons in alleviating motor symptoms in a PD mouse model using the novel inhibitory opsin eOPN3.

Background: Parkinson’s disease (PD) is a common neurodegenerative disease primarily involving basal ganglia circuitry. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established neurosurgical intervention for advanced PD. However, DBS therapeutic benefits are limited, and the stimulation is frequently associated with adverse effects. Optogenetics is a novel neuromodulation method that can outperform conventional DBS in aspects of efficacy and safety.

Method: eOPN3, a novel G protein coupled receptor inhibitory opsin, was expressed in mice STN via stereotactic injection of an adeno-associated virus expressing the opsin under the CAMKII promotor. Hemi-parkinsonism was induced by stereotactic injection of 6-hydroxydopamine (6-OHDA) to the mice striatum. Optical fiber was implanted above the STN. The opsin was photo-inhibited by external green LED light through the optical fiber cannula. Motor activity was tested in the open field before, during and after stimulation. Gait kinematics were collected in the anterior and lateral planes during treadmill locomotion before and during stimulation.

Results: Left hemi-parkinsonism with unilateral left eOPN3 opsin were expressed in the STN of 8 wild-type mice. Before stimulation, the mice exhibited an Ipsi-lesional versive bias in their free locomotion. After photo-inhibition, all mice exhibited bidirectional movements, with significant contra-lesional versive bias in their free locomotion. Optogenetic inhibition also significantly increased movement velocity and distance traveled by the mice. Machine-learning based gait analysis showed measurable alterations in spatio-temporal gait parameters compared to control mice, in concert with the expected motor deficits.

Conclusion: Optogenetic deep brain stimulation (OPTO-DBS) direct suppression of the STN via eOPN3 alleviated motor symptoms in this PD mouse model. Further research exploring how distinct neuronal populations within the STN subserve different aspects of motor function is essential to achieve optimal DBS targeting for advanced PD patients, optimizing clinical outcomes while minimizing stimulation off target effects.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/optogenetic-mediated-inhibition-of-the-subthalamic-nucleus-alleviates-motor-symptoms-in-experimental-hemi-parkinsonism-mouse-model/