Subthalamic nucleus electrical stimulation modulates calcium activity of nigral astrocytes.

Elodie Barat,Céline Bouyssières,Florence Appaix,Mireille Albrieux,Marc Savasta,Sylvie Boisseau,David I Finkelstein

doi:10.1371/journal.pone.0041793

Abstract

BackgroundThe substantia nigra pars reticulata (SNr) is a major output nucleus of the basal ganglia, delivering inhibitory efferents to the relay nuclei of the thalamus. Pathological hyperactivity of SNr neurons is known to be responsible for some motor disorders e.g. in Parkinson's disease. One way to restore this pathological activity is to electrically stimulate one of the SNr input, the excitatory subthalamic nucleus (STN), which has emerged as an effective treatment for parkinsonian patients. The neuronal network and signal processing of the basal ganglia are well known but, paradoxically, the role of astrocytes in the regulation of SNr activity has never been studied.Principal FindingsIn this work, we developed a rat brain slice model to study the influence of spontaneous and induced excitability of afferent nuclei on SNr astrocytes calcium activity. Astrocytes represent the main cellular population in the SNr and display spontaneous calcium activities in basal conditions. Half of this activity is autonomous (i.e. independent of synaptic activity) while the other half is dependent on spontaneous glutamate and GABA release, probably controlled by the pace-maker activity of the pallido-nigral and subthalamo-nigral loops. Modification of the activity of the loops by STN electrical stimulation disrupted this astrocytic calcium excitability through an increase of glutamate and GABA releases. Astrocytic AMPA, mGlu and GABAA receptors were involved in this effect.SignificanceAstrocytes are now viewed as active components of neural networks but their role depends on the brain structure concerned. In the SNr, evoked activity prevails and autonomous calcium activity is lower than in the cortex or hippocampus. Our data therefore reflect a specific role of SNr astrocytes in sensing the STN-GPe-SNr loops activity and suggest that SNr astrocytes could potentially feedback on SNr neuronal activity. These findings have major implications given the position of SNr in the basal ganglia network.

Highlights

The pars reticulata of the substantia nigra (SNr) is the main output nucleus of the basal ganglia network and conveys the final output signal to the thalamus and brain stem [1]
We found that substantia nigra pars reticulata (SNr) astrocytes displayed spontaneous calcium activity in basal conditions
The pallido-nigral and subthalamo-nigral loops have a crucial influence on the spontaneous activity of SNr neurons and we wondered about their impact on astrocyte activity

Summary

Introduction

The pars reticulata of the substantia nigra (SNr) is the main output nucleus of the basal ganglia network and conveys the final output signal to the thalamus and brain stem [1]. The SNr may be considered as a gateway in the transmission of information to the motor and cognitive systems This output nucleus mostly integrates inputs from the striatum, the external segment of globus pallidus (GPe) and the subthalamic nucleus (STN). The cellular mechanisms of STNHFS are still debated but it has been proposed that HFS could inactivate STN neurons [9,10] or change their abnormal firing mode into recurrent bursting activity [11]. This normalization could reduce the hyperactivity of basal ganglia output structures, such as SNr [12,13,14]. The neuronal network and signal processing of the basal ganglia are well known but, paradoxically, the role of astrocytes in the regulation of SNr activity has never been studied

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Conclusion