Deep brain stimulation-guided optogenetic rescue of parkinsonian symptoms

Sébastien Valverde,Asier Aristieta Arbelaiz,Bertrand Degos,Willy Derousseaux,Giuseppe Gangarossa,Jonathan Touboul,Marie Vandecasteele,Laurent Venance,Charlotte Piette

doi:10.1038/s41467-020-16046-6

Abstract

Deep brain stimulation (DBS) of the subthalamic nucleus is a symptomatic treatment of Parkinson’s disease but benefits only to a minority of patients due to stringent eligibility criteria. To investigate new targets for less invasive therapies, we aimed at elucidating key mechanisms supporting deep brain stimulation efficiency. Here, using in vivo electrophysiology, optogenetics, behavioral tasks and mathematical modeling, we found that subthalamic stimulation normalizes pathological hyperactivity of motor cortex pyramidal cells, while concurrently activating somatostatin and inhibiting parvalbumin interneurons. In vivo opto-activation of cortical somatostatin interneurons alleviates motor symptoms in a parkinsonian mouse model. A computational model highlights that a decrease in pyramidal neuron activity induced by DBS or by a stimulation of cortical somatostatin interneurons can restore information processing capabilities. Overall, these results demonstrate that activation of cortical somatostatin interneurons may constitute a less invasive alternative than subthalamic stimulation.

Highlights

Deep brain stimulation (DBS) of the subthalamic nucleus is a symptomatic treatment of Parkinson’s disease but benefits only to a minority of patients due to stringent eligibility criteria
We showed that DBS normalized pathological hyperactivity of motor cortex pyramidal cells, while concurrently inhibiting parvalbumin (PV)- and activating somatostatin (SST)expressing GABAergic interneurons
In 6-OHDA-lesioned rats, we found that the increased firing activity was diminished by DBS (p = 0.0311, n = 20) back to physiological firing rates (Fig. 1b), with 68% of pyramidal cells inhibited by DBS (Fig. 1c)

Summary

Introduction

Deep brain stimulation (DBS) of the subthalamic nucleus is a symptomatic treatment of Parkinson’s disease but benefits only to a minority of patients due to stringent eligibility criteria. The main symptomatic treatment for Parkinson’s disease consists in substituting lacking dopamine with levodopa and/or dopaminergic agonists, but after a typical “honeymoon” period with dopaminergic therapy, patients inevitably develop motor complications[1] At this stage, deep brain stimulation at high frequency of the subthalamic nucleus (DBS) constitutes to date the most efficient symptomatic treatment[2,3]. We showed that DBS normalized pathological hyperactivity of motor cortex pyramidal cells, while concurrently inhibiting parvalbumin (PV)- and activating somatostatin (SST)expressing GABAergic interneurons Reproducing these effects by direct opto-activation of cortical SST interneurons alleviates motor symptoms in a parkinsonian mouse model. Our computational model shows that the dampening of the firing activity of pyramidal cells by DBS and DBS-guided optogenetics restores cortical information processing capabilities Overall, these results establish that cortical SST interneurons constitute a promising target for a less invasive alternative to DBS

Methods

Results

Conclusion