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1 Acta Neurobiologiae Experimentalis

1 2019

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Striatal GABA transporter activity governs dopamine transmission and shows maladaptive downregulation in a mouse model of Parkinsonism

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Roberts B. , Doig N. , Brimblecombe K. , Wade-Martins R. , Magill P. , Cragg S.

nr Suppl.1

Dopamine (DA) release in the striatum is directly gated by mechanisms operating on striatal axons. We recently demonstrated that DA release is under tonic inhibition by a striatal GABA source. Given the paucity of GABAergic axoaxonic synapses on DA axons, this striatal GABA tone presumably arises from ambient GABA. GABA can provide an ambient tone on GABAergic striatal projection neurons at a level limited by striatal plasma membrane GABA transporters (GATs) but whether GATs determine DA output has been unknown. We reveal that GAT‑1 and GAT‑3 strongly regulate DA release in mouse striatum by limiting the GABA tone on DA axons in dorsolateral striatum (DLS) but not nucleus accumbens core (NAcC). We find correspondingly greater GAT‑1 and GAT‑3 levels in DLS than NAcC. Further, we demonstrate that GAT‑1 and GAT‑3 located at least in part on astrocytes are critical to the level of GABA inhibition of DA release, as astrocyte inactivation prevented the effects of GAT inhibition. Moreover, in a human alpha‑synuclein‑overexpressing mouse model of parkinsonism, we find that tonic inhibition of DA release by GABA is augmented in DLS but not NAcC as a consequence of decreased GAT levels. Altogether, these data indicate that striatal GATs determine the level of GABA inhibition of DA release in a region‑specific manner that supports DA release in DLS, and that GATs are a site of maladaptive plasticity in a model of Parkinson’s that limits DA output.