Disruption of dopaminergic transmission remodels tripartite synapse morphology and astrocytic calcium activity within substantia nigra pars reticulata

Abstract

The substantia nigra pars reticulata (SNr) is a major output nucleus of the basal ganglia circuitry particularly sensitive to pathological dopamine depletion. Indeed, hyperactivity of SNr neurons is known to be responsible for some motor disorders characteristic of Parkinson's disease. The neuronal processing of basal ganglia dysfunction is well understood but, paradoxically, the role of astrocytes in the regulation of SNr activity has rarely been considered. We thus investigated the influence of the disruption of dopaminergic transmission on plastic changes at tripartite glutamatergic synapses in the rat SNr and on astrocyte calcium activity. In 6-hydroxydopamine-lesioned rats, we observed structural plastic changes of tripartite glutamatergic synapses and perisynaptic astrocytic processes. These findings suggest that subthalamonigral synapses undergo morphological changes that accompany the pathophysiological processes of Parkinson's disease. The pharmacological blockade of dopaminergic transmission (with sulpiride and SCH-23390) increased astrocyte calcium excitability, synchrony and gap junction coupling within the SNr, suggesting a functional adaptation of astrocytes to dopamine transmission disruption in this output nucleus. This hyperactivity is partly reversed by subthalamic nucleus high-frequency stimulation which has emerged as an efficient symptomatic treatment for Parkinson's disease. Therefore, our results demonstrate structural and functional reshaping of neuronal and glial elements highlighting a functional plasticity of neuroglial interactions when dopamine transmission is disrupted.

Keywords: DBS; Parkinson; astrocyte; calcium; dopamine; synchrony.