Abstract
The prevailing circuit model predicts that hyperactivity of the striatopallidal pathway and subsequently increased inhibition of external globus pallidus (GPe) neurons lead to the hypokinetic symptoms of Parkinson's disease (PD). It is believed that hyperactivity ofthe striatopallidal pathway is due to inactivity of dopamine receptors on the somatodendritic membrane of striatopallidal neurons, but the exact cellular underpinnings remain unclear. In this study, we show that mouse GPe astrocytes critically control ambient glutamate level, which in turn gates striatopallidal transmission via the activation of presynaptic metabotropic glutamate receptors. This presynaptic inhibition of striatopallidal transmission is diminished after the chronic loss of dopamine. Elevation of intracellular glutamate content in astrocytes restores the proper regulation of the striatopallidal input in PD models. These findings argue that astrocytes are key regulators of the striatopallidal synapse. Targeting this cell class may serve as an alternative therapeutic strategy for PD.
Highlights
Astrocytes are integral elements of neural circuits
GPe astrocytes are regulated by dopamine In keeping with the previous findings of astrocyte enrichment in the GPe, high levels of GFAP were observed in this brain area
The astrocyte-to-neuron ratio was an order of magnitude higher in the GPe than in the dorsal striatum (GPe=1.8±0.4; dStr=0.13±0.03; P
Summary
Astrocytes are integral elements of neural circuits. Previous studies suggest astrocytes are enriched in the external globus pallidus (GPe) of the basal ganglia (Lange et al, 1976; Salvesen et al, 2015). This abundance implies that astrocytes may play a crucial role in regulating GPe function. Ultrastructural studies suggest that GPe astrocytic processes are juxtaposed to striatopallidal terminals and are poised to regulate striatopallidal synaptic transmission (Galvan et al, 2010). While GPe astrocytes are likely vital in supporting striatopallidal transmission via the clearance and recycling of important substrates, it is unclear whether they actively control striatopallidal transmission. Since hyperactive striatopallidal signaling is thought to underlie hypokinetic symptoms of PD (Kravitz et al, 2010; Lemos et al, 2016), we sought to determine if disruption of astrocytic regulation could account for this altered circuit behavior in PD
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