Objective: Using opto-activation of cortical interneurons, we aimed at mimicking the cortical effects of deep brain stimulation of the subthalamic nucleus (STN-DBS) to reproduce its therapeutic benefits, thus paving the way for less invasive approaches. Background: Results: Conclusions:

Background: Motor symptoms of Parkinson’s disease result from the degeneration of the nigro-striatal dopaminergic pathway. The treatment for Parkinson’s disease is mainly symptomatic consisting in the replacement of the lacking dopamine with levodopa and dopaminergic agonists. However, after the “honeymoon” relief period with dopaminergic therapy, patients ineluctably develop levodopa-induced motor complications. At this stage, STN-DBS constitutes a very efficient alternative therapy. However, due to its surgical invasiveness and strict eligibility criteria, STN-DBS benefits only to a minority of patients (~5-10%). Several hypotheses have been proposed to explain the beneficial effects of STN-DBS. Notably, a growing body of evidence points towards a cortical effect of STN-DBS in parkinsonian rodent models and patients.

Method: In anaesthetized in vivo rodents (mice and rat), we performed intra- and juxtacellular electrophysiological recordings of pyramidal cells and interneurons of the motor cortex. We used sham and parkinsonian animal (6-OHDA), and, in some experiments, transgenic mice allowing to optogenetically manipulate cortical somatostatin or parvalbumin interneurons. We also developed a mathematical model of the cortical effects of STN-DBS and interneuron opto-activation.

Results: Using in vivo electrophysiology, optogenetics and modeling, we found that subthalamic stimulation normalizes pathological hyperactivity of motor cortex pyramidal cells, while concurrently activating somatostatin and inhibiting parvalbumin interneurons. Furthermore, we reproduced these effects by direct opto-activation of somatostatin interneurons allowing the alleviation of motor symptoms in a 6-OHDA parkinsonian mouse model.

Conclusion: Overall, these results demonstrate that activation of cortical somatostatin interneurons may constitute an alternative and less invasive therapy compared to subthalamic stimulation.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/deep-brain-stimulation-guided-optogenetic-rescue-of-parkinsonian-symptoms/