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Astrocytes are increasingly appreciated to possess underestimated and important roles in modulating neuronal circuits. Astrocytes in striatum can regulate dopamine transmission by governing the extracellular tone of axonal neuromodulators, including GABA and adenosine. However, here we reveal that striatal astrocytes occupy a cell type-specific anatomical and functional relationship with cholinergic interneurons (ChIs), through which they rapidly excite ChIs and govern dopamine release via nicotinic acetylcholine receptors on subsecond timescales. We identify that ChI somata are in unexpectedly close proximity to astrocyte somata, in mouse and human, forming a "soma-to-soma" satellite-like configuration not typically observed for other striatal neurons. We find that transient depolarization of astrocytes in mouse striatum reversibly regulates ChI excitability by decreasing extracellular calcium. These findings reveal a privileged satellite astrocyte-interneuron interaction for striatal ChIs operating on subsecond timescales via regulation of extracellular calcium dynamics to shape downstream striatal circuit activity and dopamine signaling. Astrocytes perform intriguing roles in neural circuits. Here, the authors show that in striatum, astrocytes adopt a satellite-like proximity to cholinergic interneurons, modulating excitability and downstream dopamine release on subsecond timescales. [ABSTRACT FROM AUTHOR]

Striatal fast-spiking interneurons (FSIs) potently inhibit the output neurons of the striatum and, as such, powerfully modulate action learning. Through electrical synaptic coupling, FSIs are theorized to temporally coordinate their activity. This has important implications for their ability to temporally summate inhibition on downstream striatal projection neurons. While some in vivo single-unit electrophysiological recordings of putative FSIs support coordinated firing, others do not. Moreover, it is unclear as to what aspect of action FSIs encode. To address this, we used in vivo calcium imaging of genetically identified FSIs in freely moving mice and applied machine learning analyses to decipher the relationship between FSI activity and movement. We report that FSIs exhibit ensemble activity that encodes the speed of action sub-components, including ambulation and head movements. These results suggest FSI population dynamics fit within a Hebbian model for ensemble inhibition of striatal output guiding action. [ABSTRACT FROM AUTHOR]

Striatal dopamine (DA) is critical for action and learning. Recent data show that DA release is under tonic inhibition by striatal GABA. Ambient striatal GABA tone on striatal projection neurons can be determined by plasma membrane GABA uptake transporters (GATs) located on astrocytes and neurons. However, whether striatal GATs and astrocytes determine DA output are unknown. We reveal that DA release in mouse dorsolateral striatum, but not nucleus accumbens core, is governed by GAT-1 and GAT-3. These GATs are partly localized to astrocytes, and are enriched in dorsolateral striatum compared to accumbens core. In a mouse model of early parkinsonism, GATs are downregulated, tonic GABAergic inhibition of DA release augmented, and nigrostriatal GABA co-release attenuated. These data define previously unappreciated and important roles for GATs and astrocytes in supporting DA release in striatum, and reveal a maladaptive plasticity in early parkinsonism that impairs DA output in vulnerable striatal regions. GABA transporters expressed in the striatum may affect behaviour. Here the authors investigate the contribution of GABA transporters on astrocytes to the regulation of dopamine release in the striatum, and show decreased expression of GAT-1 and GAT-3 in a mouse model of Parkinsonism. [ABSTRACT FROM AUTHOR]

Mesostriatal dopaminergic neurons possess extensively branched axonal arbours. Whether action potentials are converted to dopamine output in the striatum will be influenced dynamically and critically by axonal properties and mechanisms that are poorly understood. Here, we address the roles for mechanisms governing release probability and axonal activity in determining short‐term plasticity of dopamine release, using fast‐scan cyclic voltammetry in the ex vivo mouse striatum. We show that brief short‐term facilitation and longer short term depression are only weakly dependent on the level of initial release, i.e. are release insensitive. Rather, short-term plasticity is strongly determined by mechanisms which govern axonal activation, including K+‐gated excitability and the dopamine transporter, particularly in the dorsal striatum. We identify the dopamine transporter as a master regulator of dopamine short‐term plasticity, governing the balance between release‐dependent and independent mechanisms that also show region‐specific gating. Dopamine release in the striatum has important roles in action selection and in disorders such as Parkinson's disease. The authors here show that short-term plasticity of dopamine release is strongly determined by axonal activation and dopamine transporters. [ABSTRACT FROM AUTHOR]