Cortical somatostatin interneurons as a therapeutic target in Parkinson’ disease – SMASHPARK

In Parkinson’s disease, deep brain stimulation of the subthalamic nucleus (DBS-STN) is an effective treatment but benefits only to 5-10% of patients mostly because of its invasive neurosurgery. It is thus crucial to identify less invasive therapeutic targets that could benefit the greatest number of patients. A growing body of evidence points towards a cortical effect of DBS-STN, and hyperactivity of pyramidal neurons may be a neuropathological hallmark in Parkinson’s disease. We reasoned that mimicking the cortical effects of DBS-STN should reproduce its therapeutic benefits, thus paving the way for less invasive approaches benefiting the greatest number.
We recently found that DBS-STN normalises pathological hyperactivity of motor cortex pyramidal cells, while activating GABAergic somatostatin and inhibiting parvalbumin interneurons. We show that in vivo opto-activation of cortical somatostatin cells alleviates motor symptoms in a parkinsonian mouse model (Valverde et al., 2020). Overall, this demonstrates that activation of cortical somatostatin interneurons is a promising target to alleviate the motor dysfunctions in a parkinsonian rodent model and may constitute a less invasive alternative than subthalamic stimulation.
Our project is now to further analyse the effects of somatostatin interneurons on pyramidal cell pathological hyperactivity and membrane properties, and then perform trans-cranial optogenetic stimulation of somatostatin cells with a wearable device of a micro-LED array, optimize the stimulation parameters, and develop an adaptive closed-loop stimulation in two parkinsonian models: 6-OHDA rodents (Team 1) and MPTP non-human primates (Team 2). For this purpose, we will combine in vivo electrophysiology & two-photon-imaging, optogenetics, mathematical modelling and behavioural tasks.
Our project should pave the way for proposing an alternative to DBS-STN that could benefit the largest number of Parkinsonian patients.