AUTHOR=Madadi Asl Mojtaba , Asadi  Atefeh , Enayati  Jamil , Valizadeh  Alireza 

TITLE=Inhibitory Spike-Timing-Dependent Plasticity Can Account for Pathological Strengthening of Pallido-Subthalamic Synapses in Parkinson’s Disease

JOURNAL=Frontiers in Physiology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2022.915626

DOI=10.3389/fphys.2022.915626

ISSN=1664-042X

ABSTRACT=‎Parkinson's disease (PD) is a neurodegenerative brain disorder associated with dysfunction of the basal ganglia (BG) circuitry‎. ‎Dopamine (DA) depletion in experimental PD models leads to the pathological strengthening of pallido-subthalamic synaptic connections‎, ‎contributing to the emergence of abnormally synchronized neuronal activity in the external segment of the globus pallidus (GPe) and subthalamic nucleus (STN)‎. ‎Augmented GPe-STN transmission following loss of DA was attributed to heterosynaptic plasticity mechanisms induced by cortico-subthalamic inputs‎. However‎, ‎synaptic plasticity may play a role in this process. Here‎, ‎by employing computational modeling we show that assuming inhibitory spike-timing-dependent plasticity (iSTDP) at pallido-subthalamic synapses can account for pathological strengthening of pallido-subthalamic synapses in PD by further promoting correlated neuronal activity in the GPe-STN network‎. ‎In addition‎, ‎we show that GPe-STN transmission delays can shape bistable activity-connectivity states due to iSTDP, characterized by strong connectivity and strong synchronized activity (pathological states) ‎as ‎opposed ‎to‎ weak connectivity and desynchronized activity (physiological states)‎. ‎Our results may shed light on how abnormal reshaping of GPe-STN connectivity by synaptic plasticity during parkinsonism is related to the PD pathophysiology and contribute to the development of therapeutic brain stimulation techniques targeting plasticity-induced rewiring of network connectivity.