GABA uptake transporters support dopamine release in dorsal striatum with maladaptive downregulation in a parkinsonism model

Roberts, Bradley M.; Doig, Natalie M.; Brimblecombe, Katherine R.; Lopes, Emanuel F.; Siddorn, Ruth E.; Threlfell, Sarah; Connor-Robson, Natalie; Bengoa-Vergniory, Nora; Pasternack, Nicholas; Wade‐Martins, Richard; Magill, Peter J.; Cragg, Stephanie J.

doi:10.1038/s41467-020-18247-5

Cited by 34 publications

(93 citation statements)

References 61 publications

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“…However, conclusive anatomical evidence for GABA A and GABA B receptors located on confirmed DA axons has not yet been reported. Direct electrophysiological recordings of nigrostriatal axons strongly support the presence of functional GABA A in DA axons [ 47 ], as do the findings that GABA A and GABA B agonists and antagonists can respectively suppress and enhance DA release when evoked by discrete single electrical or optogenetic stimulus pulses of ChR2-expressing DA axons [ 34 , 36 , 37 , 39 ]. These brief (≤2 ms) and targeted stimulation paradigms would offer very limited opportunity for activation of other striatal circuits to impact on DA released by the same stimulus.…”

Section: Direct Vs Indirect Actions Of Gaba a mentioning

confidence: 99%

“…Moreover, very recent studies in striatal slices have revealed that endogenous striatal GABA, across dorsal-ventral striatal territories, provides a tonic inhibition of DA release. When short single optogenetic stimulus pulses were used to activate ChR2-expressing DA axons and limit co-activation of other local neurons [ 38 ], both GABA A and GABA B receptor antagonists independently enhanced DA release [ 36 , 37 , 39 ]. Altogether, these findings demonstrate that endogenous GABA locally released in striatum can act at both GABA A and GABA B receptors to inhibit DA release, and this inhibition can operate tonically.…”

Section: Gaba a And Gaba B Rmentioning

confidence: 99%

“…GABA receptor activation also has modest but significant effects on the frequency sensitivity of DA release. GABA A and GABA B receptor activation interacted with frequency and number of stimulus pulses to slightly promote the ratio of DA release evoked by high-frequency trains over single pulse release (see Figure 1 ) [ 36 , 37 , 39 ]. This outcome is consistent with a reduction in the initial release probability of DA, and consequentially, a slight relief of short-term depression.…”

Section: Gaba a And Gaba B Rmentioning

confidence: 99%

“…These brief (≤2 ms) and targeted stimulation paradigms would offer very limited opportunity for activation of other striatal circuits to impact on DA released by the same stimulus. Furthermore, a candidate mechanism whereby GABA receptors on glutamate afferents operate as an intermediary is unlikely, as the enhancement of evoked DA release by GABA receptor antagonists does not require striatal glutamate receptors [ 39 ]. A mechanism involving GABA receptors located on GABAergic interneurons is also unlikely, as GABA receptor agonists would be expected to suppress GABAergic interneurons and therefore enhance DA output.…”

Section: Direct Vs Indirect Actions Of Gaba a mentioning

confidence: 99%

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Axonal Modulation of Striatal Dopamine Release by Local γ-Aminobutyric Acid (GABA) Signalling

Roberts

Lopes

Cragg

2021

Cells

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Striatal dopamine (DA) release is critical for motivated actions and reinforcement learning, and is locally influenced at the level of DA axons by other striatal neurotransmitters. Here, we review a wealth of historical and more recently refined evidence indicating that DA output is inhibited by striatal γ-aminobutyric acid (GABA) acting via GABAA and GABAB receptors. We review evidence supporting the localisation of GABAA and GABAB receptors to DA axons, as well as the identity of the striatal sources of GABA that likely contribute to GABAergic modulation of DA release. We discuss emerging data outlining the mechanisms through which GABAA and GABAB receptors inhibit the amplitude as well as modulate the short-term plasticity of DA release. Furthermore, we highlight recent data showing that DA release is governed by plasma membrane GABA uptake transporters on striatal astrocytes, which determine ambient striatal GABA tone and, by extension, the tonic inhibition of DA release. Finally, we discuss how the regulation of striatal GABA-DA interactions represents an axis for dysfunction in psychomotor disorders associated with dysregulated DA signalling, including Parkinson’s disease, and could be a novel therapeutic target for drugs to modify striatal DA output.

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Section: Direct Vs Indirect Actions Of Gaba a mentioning

confidence: 99%

Section: Gaba a And Gaba B Rmentioning

confidence: 99%

Section: Gaba a And Gaba B Rmentioning

confidence: 99%

Section: Direct Vs Indirect Actions Of Gaba a mentioning

confidence: 99%

See 2 more Smart Citations

Axonal Modulation of Striatal Dopamine Release by Local γ-Aminobutyric Acid (GABA) Signalling

Roberts

Lopes

Cragg

2021

Cells

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“…55 Further, a recent study demonstrated that enhanced GABA tone in slice can mediate a ~50% reduction in DA release similar to that observed in Tor1a +/ΔE knockin mice. 56 To determine if increased GABA B receptor activation and/or increased GABA tone mediates the reduction in DA release in Tor1a +/ΔE knockin mice, we performed a dose response experiment with the selective GABA B antagonist CGP 88584. CGP 88584 dose-dependently enhanced DA release in both Tor1a +/+ and Tor1a +/ΔE mice (Fig 6B).…”

Section: Gaba B Receptor Function In Tor1a +/δE Micementioning

confidence: 99%

Cell-intrinsic effects of TorsinA(ΔE) disrupt dopamine release in a mouse model of DYT1-TOR1A dystonia

Downs

Fan

Kadakia

et al. 2020

Preprint

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DYT1-TOR1A dystonia is an inherited dystonia caused by a three base-pair deletion in the TOR1A gene (TOR1AΔE). Although the mechanisms underlying the dystonic movements are largely unknown, abnormalities in striatal dopamine and acetylcholine neurotransmission are consistently implicated whereby dopamine release is reduced while cholinergic tone is increased. Because striatal cholinergic neurotransmission mediates dopamine release, it is not known if the dopamine release deficit is mediated indirectly by abnormal acetylcholine neurotransmission or if Tor1a(ΔE) acts directly within dopaminergic neurons to attenuate release. To dissect the microcircuit that governs the deficit in dopamine release, we conditionally expressed Tor1a(ΔE) in either dopamine neurons or cholinergic interneurons in mice and assessed striatal dopamine release using ex vivo fast scan cyclic voltammetry or dopamine efflux using in vivo microdialysis. Conditional expression of Tor1a(ΔE) in cholinergic neurons did not affect striatal dopamine release. In contrast, conditional expression of Tor1a(ΔE) in dopamine neurons reduced dopamine release to 50% of normal, which is comparable to the deficit in Tor1a+/ΔE knockin mice that express the mutation ubiquitously. Despite the deficit in dopamine release, we found that the Tor1a(ΔE) mutation does not cause obvious nerve terminal dysfunction as other presynaptic mechanisms, including electrical excitability, vesicle recycling/refilling, Ca2+ signaling, D2 dopamine autoreceptor function and GABAB receptor function, are intact. Although the mechanistic link between Tor1a(ΔE) and dopamine release is unclear, these results clearly demonstrate that the defect in dopamine release is caused by the action of the Tor1a(ΔE) mutation within dopamine neurons.

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Putaminal y‐Aminobutyric Acid Modulates Motor Response to Dopaminergic Therapy in Parkinson's Disease

et al. 2021

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Background: Motor response to dopaminergic therapy is a characteristic of patients with Parkinson's disease (PD). Whether nondopaminergic neurotransmitters contribute to treatment response is uncertain.Objectives: The aim of this study is to determine whether putaminal y-aminobutyric acid (GABA) levels are associated with dopaminergic motor response. Methods: We assessed putaminal GABA levels in 19 PD patients and 13 healthy controls (HCs) utilizing ultra-high field proton magnetic resonance spectroscopy. Motor performance was evaluated using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale, Part III, in the ON and OFF states. Statistical analysis comprised group comparisons, correlation analysis, and multiple linear regression. Results: In PD, GABA levels were significantly higher compared to HCs (1.50 AE 0.26 mM vs. 1.26 AE 0.31 mM, P = 0.022). Furthermore, GABA levels were independent predictors of absolute and relative dopaminergic treatment response. Conclusions: Our findings indicate that elevated putaminal GABA levels are associated with worse dopaminergic response in PD, emphasizing the essential role of nondopaminergic neurotransmitters in motor response.

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GABA uptake transporters support dopamine release in dorsal striatum with maladaptive downregulation in a parkinsonism model

Cited by 34 publications

References 61 publications

Axonal Modulation of Striatal Dopamine Release by Local γ-Aminobutyric Acid (GABA) Signalling

Axonal Modulation of Striatal Dopamine Release by Local γ-Aminobutyric Acid (GABA) Signalling

Cell-intrinsic effects of TorsinA(ΔE) disrupt dopamine release in a mouse model of DYT1-TOR1A dystonia

Putaminal y‐Aminobutyric Acid Modulates Motor Response to Dopaminergic Therapy in Parkinson's Disease

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