Dynamical modeling reveals the pivotal regulatory role of direct glutamatergic subthalamic-striatal projections in modulating basal ganglia activity during absence epilepsy

Abstract

Increasing anatomical evidence suggests the existence of direct glutamatergic projections originating from the subthalamic nucleus (STN) to the striatum. However, due to the complex structure of the striatum, unraveling the impact of these subthalamostriatal projections on the functionality of the basal ganglia remains a critical and urgent task. In this paper, we conduct a comprehensive investigation into the potential role of subthalamostriatal projections in regulating absence epilepsy (AE) within a dynamic computational framework. Our findings reveal that, when the subthalamostriatal projections are disconnected within the model, the striatal output exhibits no notable regulatory influence on AE. Interestingly, the subthalamostriatal projections play a significant role in managing AE. Moreover, the directly striatum-connected pathways, which significantly influence striatal output, actively participate in the control of AE through modulation by the subthalamostriatal projections. And, the control effects of other indirectly striatum-connected basal ganglia pathways on AE are significantly influenced by the subthalamostriatal projections. Furthermore, the biologically plausible range of coupling weights on subthalamostriatal projections can be effectively estimated within the model. Crucially, our analysis indicates that striatal-related pathways regulate AE by significantly influencing the activation levels of basal ganglia nuclei. The striatal nuclei exhibit distinct high and low triggering average discharge rates, thus making it a potential effective target for clinical treatment of AE. Taking AE as an exemplar, we underscore the pivotal and non-negligible role played by subthalamostriatal projections in modulating basal ganglia functionality, potentially serving as a source of inspiration for future experimental research endeavors.