GABA co-released from striatal dopamine axons dampens phasic dopamine release through autoregulatory GABAA receptors

Patel, Jyoti C.; Sherpa, Ang D.; Melani, Riccardo; Witkovsky, Paul; Wiseman, Madeline R.; O’Neill, Brian; Aoki, Chiye; Tritsch, Nicolas X.; Rice, Margaret E.

doi:10.1016/j.celrep.2024.113834

Cited by 6 publications

(4 citation statements)

References 138 publications

(220 reference statements)

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“…The striatum is a predominantly GABAergic structure consisting of mostly GABAergic medium spiny neurons along with a variety of GABAergic interneurons, each with a unique connectivity pattern to the surrounding circuitry (Taverna et al, 2008; Dobbs et al, 2016; Tepper et al, 2018; Dorst et al, 2020; Holly et al, 2021; Kocaturk et al, 2022). As a result, there are many possible sources of GABA within the striatum, including these GABAergic neurons, non-neuronal cells, co-release from DA axons, and co-release from CINs – any combination of which could be contributing to the effects observed here (Tritsch et al, 2012; Wójtowicz et al, 2013; Lozovaya et al, 2018; Roberts et al, 2020; Patel et al, 2024). Recently, Patel and colleagues showed that GABA co-released from DA axons can inhibit the same axons via autoregulatory GABA A receptors (Patel et al, 2024).…”

Section: Discussionmentioning

confidence: 98%

“…As a result, there are many possible sources of GABA within the striatum, including these GABAergic neurons, non-neuronal cells, co-release from DA axons, and co-release from CINs -any combination of which could be contributing to the effects observed here (Tritsch et al, 2012;Wójtowicz et al, 2013;Lozovaya et al, 2018;Roberts et al, 2020;Patel et al, 2024). Recently, Patel and colleagues showed that GABA co-released from DA axons can inhibit the same axons via autoregulatory GABAA receptors (Patel et al, 2024). Together with the data presented here and past results showing that CINs can drive GABA release from DA axons (Nelson et al, 2014), this feature could endow the CIN-DA axon striatal circuit with a complex means of intrinsic negative feedback.…”

Section: Gabaergic Control Over Da Axon Excitabilitymentioning

confidence: 99%

“…Several studies have demonstrated that various neurotransmitters are poised to locally modulate DA release via axonal receptors (Kennedy et al, 1992; Chen et al, 2001; H. Zhang & Sulzer, 2003; Shin et al, 2015; Sulzer et al, 2016, Roberts et al, 2022). Among these receptors, ionotropic and metabotropic GABA receptors have been shown to influence DA release through multiple mechanisms including via a striatal GABAergic tone and GABA co-release from DA axons themselves (Gruen et al, 1992; Smolders et al, 1995; Pitman et al, 2014; Lopes et al, 2019; Kramer et al, 2020; Holly et al, 2021; Patel et al, 2024). Past work using direct axon recordings demonstrated that GABA A receptors are present on the axons of DA neurons and can inhibit striatal DA release by decreasing axonal excitability and hindering action potential (AP) propagation (Kramer et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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Presynaptic GABA_Areceptors control integration of nicotinic input onto dopaminergic axons in the striatum

Brill-Weil,

Kramer,

Yanez

et al. 2024

Preprint

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Axons of dopaminergic neurons express gamma-aminobutyric acid type-A receptors (GABAARs) and nicotinic acetylcholine receptors (nAChRs) which are both independently positioned to shape striatal dopamine release. Using electrophysiology and calcium imaging, we investigated how interactions between GABAARs and nAChRs influence dopaminergic axon excitability. Direct axonal recordings showed that benzodiazepine application suppresses subthreshold axonal input from cholinergic interneurons (CINs). In imaging experiments, we used the first temporal derivative of presynaptic calcium signals to distinguish between direct- and nAChR-evoked activity in dopaminergic axons. We found that GABAAR antagonism with gabazine selectively enhanced nAChR-evoked axonal signals. Acetylcholine release was unchanged in gabazine suggesting that GABAARs located on dopaminergic axons, but not CINs, mediated this enhancement. Unexpectedly, we found that a widely used GABAAR antagonist, picrotoxin, inhibits axonal nAChRs and should be used cautiously for striatal circuit analysis. Overall, we demonstrate that GABAARs on dopaminergic axons regulate integration of nicotinic input to shape presynaptic excitability.

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Section: Discussionmentioning

confidence: 98%

Section: Gabaergic Control Over Da Axon Excitabilitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Presynaptic GABA_Areceptors control integration of nicotinic input onto dopaminergic axons in the striatum

Brill-Weil,

Kramer,

Yanez

et al. 2024

Preprint

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“…It is possible that not GABA but another inhibitory transmitter is packaged into vesicles by VMAT2 and responsible for the activation of postsynaptic striatal GABAA receptors that was reported after optogenetic stimulation of DA terminals (Melani et al, 2022;Patel et al, 2024;Tritsch et al, 2012;Tritsch et al, 2014). We tested two such potential compounds in the mouse vesicle uptake, glycine and taurine, both of which are structural analogues of GABA that have been reported to activate GABAA receptors, though presumably with much weaker affinity (Jonas et al, 1998).…”

Section: Effects Of Glycine and Taurine On Vmat2mentioning

confidence: 99%

Evidence for low affinity of GABA at the vesicular monoamine transporter VMAT2 – implications for transmitter co-release from dopamine neurons

Limani,

Srinivasan,

Hanzlova

et al. 2024

Preprint

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Background and PurposeMidbrain dopamine (DA) neurons comprise a heterogeneous population of cells. For instance, some DA neurons express the vesicular glutamate transporter VGLUT2 allowing these cells to co-release DA and glutamate. Additionally, GABA may be co-released from DA neurons. However, most cells do not express the canonical machinery to synthesize GABA or the vesicular GABA transporter VGAT. Instead, GABA seems to be taken up into DA neurons by a plasmalemmal GABA transporter (GAT1) and stored in synaptic vesicles via the vesicular monoamine transporter VMAT2. Yet, it remains unclear whether GABA indeed interacts with VMAT2, or whether another transmitter could be responsible for the observed inhibitory effects attributed to GABA.Experimental ApproachWe used radiotracer flux measurements in VMAT2 expressing HEK-293 cells and synaptic vesicles from rodents to determine whether GABA qualifies as substrate at VMAT2. mRNAin situhybridization was employed to determine expression of VMAT2 and GAT1 transcripts in DA neurons of mouse and in human midbrains.Key ResultsWe found that GABA reduced uptake of VMAT2 substrates in rodent synaptic vesicle preparations from striatum and cerebellum at millimolar concentrations but had no effect in VMAT2-expressing cells indicating that key components are missing in a non-neuronal system. Roughly 60 % of murine and human DA neurons in the substantia nigra express VMAT2 and GAT1 suggesting that many may be capable of co-releasing DA and GABA.Conclusion and ImplicationOur experiments suggest that GABA is a low-affinity substrate at VMAT2 with potential implications for basal ganglia physiology and disease.Bullet point summaryWhat is already knownSubpopulations of dopamine neurons co-release glutamate and/or GABA.While glutamate is loaded into vesicles by VGLUT2, GABA co-release depends on GAT1 and VMAT2.What this study addsThe relative affinity of GABA at VMAT2 was found to be in the millimolar range.Human midbrain dopamine neurons express GAT1.Clinical significanceGABA co-release from midbrain dopamine neurons may also occur in humans.GABA co-release from dopamine neurons may play a role in neuropsychiatric diseases

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The cation channel mechanisms of subthreshold inward depolarizing currents in the VTA dopaminergic neurons and their roles in the chronic-stress-induced depression-like behavior

Wang

Zhang

et al. 2023

Preprint

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The slow-intrinsic-pacemaker dopaminergic (DA) neurons originating in the ventral tegmental area (VTA) is implicated in various mood- and emotion-related disorders, such as anxiety, fear, stress and depression. Abnormal activity of projection-specific VTA DA neurons is the key factor in the development of these disorders. Here, we describe the crucial role for the NALCN and TRPC6, non-selective cation channels in mediating the subthreshold inward depolarizing current and driving the firing of action potentials of VTA DA neurons in physiological condition. Otherwise, we demonstrate that downregulation of TRPC6 protein expression in the VTA DA neurons likely contributes to the reduced activity of projection-specific VTA DA neuron in CMUS depressive mice. Furthermore, selective knockdown of TRPC6 channels in the VTA DA neurons conferred mice with depression-like behavior. This current study suggests down-regulation of TRPC6 expression/function is involved in reduced VTA DA neuron firing and depression-like behavior in the mouse models of depression.

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GABA co-released from striatal dopamine axons dampens phasic dopamine release through autoregulatory GABAA receptors

Cited by 6 publications

References 138 publications

Presynaptic GABA_Areceptors control integration of nicotinic input onto dopaminergic axons in the striatum

Presynaptic GABA_Areceptors control integration of nicotinic input onto dopaminergic axons in the striatum

Evidence for low affinity of GABA at the vesicular monoamine transporter VMAT2 – implications for transmitter co-release from dopamine neurons

The cation channel mechanisms of subthreshold inward depolarizing currents in the VTA dopaminergic neurons and their roles in the chronic-stress-induced depression-like behavior

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GABA co-released from striatal dopamine axons dampens phasic dopamine release through autoregulatory GABAA receptors

Cited by 6 publications

References 138 publications

Presynaptic GABAAreceptors control integration of nicotinic input onto dopaminergic axons in the striatum

Presynaptic GABAAreceptors control integration of nicotinic input onto dopaminergic axons in the striatum

Evidence for low affinity of GABA at the vesicular monoamine transporter VMAT2 – implications for transmitter co-release from dopamine neurons

The cation channel mechanisms of subthreshold inward depolarizing currents in the VTA dopaminergic neurons and their roles in the chronic-stress-induced depression-like behavior

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Presynaptic GABA_Areceptors control integration of nicotinic input onto dopaminergic axons in the striatum

Presynaptic GABA_Areceptors control integration of nicotinic input onto dopaminergic axons in the striatum