Spontaneous Inhibitory Synaptic Currents Mediated by a G Protein-Coupled Receptor

Gantz, Stephanie C.; Bunzow, James R.; Williams, John T.

doi:10.1016/j.neuron.2013.04.013

Cited by 80 publications

(112 citation statements)

References 31 publications

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“…This is consistent with volume transmission and the need for pooling of multiple noradrenaline vesicles to drive ␣2-receptor activation. A recent report, however, described dopaminemediated spontaneous miniature D2-IPSCs in the VTA (Gantz et al, 2013). This indicates that vesicular dopamine release must occur adjacent to a high density of D2-receptors.…”

Section: Discussionmentioning

confidence: 87%

The Timing of Dopamine- and Noradrenaline-Mediated Transmission Reflects Underlying Differences in the Extent of Spillover and Pooling

Courtney¹,

Ford

2014

J. Neurosci.

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Metabotropic transmission typically occurs through the spillover activation of extrasynaptic receptors. This study examined the mechanisms underlying somatodendritic dopamine and noradrenaline transmission and found that the extent of spillover and pooling varied dramatically between these two transmitters. In the mouse ventral tegmental area, the time course of D2-receptor-mediated IPSCs (D2-IPSCs) was consistent between cells and was unaffected by altering stimulation intensity, probability of release, or the extent of diffusion. Blocking dopamine reuptake with cocaine extended the time course of D2-IPSCs and suggested that transporters strongly limited spillover. As a result, individual release sites contributed independently to the duration of D2-IPSCs. In contrast, increasing the release of noradrenaline in the rat locus ceruleus prolonged the duration of ␣2-receptor-mediated IPSCs even when reuptake was intact. Spillover and subsequent pooling of noradrenaline activated distal ␣2-receptors, which prolonged the duration of ␣2-IPSCs when multiple release sites were activated synchronously. By using the rapid application of agonists onto large macropatches, we determined the concentration profile of agonists underlying the two IPSCs. Incorporating the results into a model simulating extracellular diffusion predicted that the functional range of noradrenaline diffusion was nearly fivefold greater in the locus ceruleus than dopamine in the midbrain. This study demonstrates that catecholamine synapses differentially regulate the extent of spillover and pooling to control the timing of local inhibition and suggests diversity in the roles of uptake and diffusion in governing metabotropic transmission.

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Section: Discussionmentioning

confidence: 87%

The Timing of Dopamine- and Noradrenaline-Mediated Transmission Reflects Underlying Differences in the Extent of Spillover and Pooling

Courtney¹,

Ford

2014

J. Neurosci.

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“…2A). In the midbrain, vesicular DA release occurs spontaneously, without electrical stimulation, eliciting spontaneous D2R-mediated inhibitory postsynaptic currents (sIPSCs) (62). sIPSCs were also prolonged in DAT Val559 slices (WT: 380.7 ± 8.7 ms, n = 135 sIPSCs; HOM: 427.5 ± 10.9 ms, n = 150 sIPSCs, P < 0.01, Mann-Whitney) ( Fig.…”

Section: Da Neurons From Dat Val559 Mice Display Alterations In Basalmentioning

confidence: 94%

“…DAT is expressed somatodendritically on DA neurons where it can limit the ability of D2Rs to reduce DA neuron firing, because D2R activation in the midbrain is tightly controlled by reuptake (60). Vesicular somatodendritic release of DA in the substantia nigra (SN) and ventral tegmental area elicits an inhibitory postsynaptic current (IPSC) via D2R activation of a G protein-coupled inwardly rectifying potassium (GIRK) channel, which can inhibit DA neuron firing (61,62). To examine the impact of DAT Val559 on basic physiological properties of DA neurons, and D2R-mediated currents, we performed whole-cell recordings of SN DA neurons in acute brain slices.…”

Section: Da Neurons From Dat Val559 Mice Display Alterations In Basalmentioning

confidence: 99%

The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants

Mergy¹,

Gowrishankar²,

Gresch

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

113

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Despite the critical role of the presynaptic dopamine (DA) transporter (DAT, SLC6A3) in DA clearance and psychostimulant responses, evidence that DAT dysfunction supports risk for mental illness is indirect. Recently, we identified a rare, nonsynonymous Slc6a3 variant that produces the DAT substitution Ala559Val in two male siblings who share a diagnosis of attention-deficit hyperactivity disorder (ADHD), with other studies identifying the variant in subjects with bipolar disorder (BPD) and autism spectrum disorder (ASD). Previously, using transfected cell studies, we observed that although DAT Val559 displays normal total and surface DAT protein levels, and normal DA recognition and uptake, the variant transporter exhibits anomalous DA efflux (ADE) and lacks capacity for amphetamine (AMPH)-stimulated DA release. To pursue the significance of these findings in vivo, we engineered DAT Val559 knock-in mice, and here we demonstrate in this model the presence of elevated extracellular DA levels, altered somatodendritic and presynaptic D2 DA receptor (D2R) function, a blunted ability of DA terminals to support depolarization and AMPHevoked DA release, and disruptions in basal and psychostimulant-evoked locomotor behavior. Together, our studies demonstrate an in vivo functional impact of the DAT Val559 variant, providing support for the ability of DAT dysfunction to impact risk for mental illness.T he neurotransmitter dopamine (DA) plays a key role in regulating brain circuits that control reward, attention, and locomotor activity (1-3), Accordingly, dopaminergic dysfunction is believed to contribute to several neuropsychiatric disorders including Parkinson's disease (4), bipolar disorder (BPD) (5), drug abuse and addiction (6), and attention-deficit hyperactivity disorder (ADHD) (7,8). The presynaptic DA transporter (DAT) is the primary mechanism for terminating DA signaling at the synapse (9) and is the primary target for several psychostimulant drugs including cocaine (COC), methylphenidate (MPH), and amphetamine (AMPH). COC and MPH are DAT antagonists, elevating extracellular DA levels by preventing DAT-mediated DA reuptake (10). AMPH actions are more complex (11). AMPH is structurally similar to DA and, as a result, is transported by DAT, competing with DA during the reuptake process. AMPH also induces DAT-mediated nonvesicular release, also termed "DA efflux," a process that involves the actions of intracellular signaling proteins such as CamKIIα (12-16) and , alterations in interactions with DAT-associated proteins and phospholipids (12,14,20), and changes in DAT phosphorylation (12,16,(21)(22)(23)) that biases the transporter toward an efflux-competent mechanism. Despite their mechanistic differences, MPH and AMPH both rapidly elevate DA in the CNS and are components of the most frequently prescribed medications for ADHD, Ritalin and Adderall, respectively. The DA modulatory actions of MPH and AMPH reinforce hypotheses derived from brain imaging studies (24) and the analysis of common genetic variation (25-30)...

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“…Also unknown are how disorders of the nervous system affect somatodendritic DA release, or how somatodendritic DA release might contribute to disorders. Drugs of abuse can also alter somatodendritic DA release, suggesting a role in addiction, as in recent studies showing that a single dose of cocaine can induce long-term potentiation of spontaneous D2-IPSCs in SNc DA neurons [36]. DA neurons are also the primary targets of as yet unknown processes that cause neurodegeneration in PD, with greater susceptibility of ventral tier SNc DA neurons versus dorsal tier or VTA DA neurons.…”

Section: Conclusion and Open Questionsmentioning

confidence: 98%

Somatodendritic dopamine release: recent mechanistic insights

Rice

Patel

2015

Phil. Trans. R. Soc. B

102

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One contribution of 16 to a discussion meeting issue 'Release of chemical transmitters from cell bodies and dendrites of nerve cells'. Dopamine (DA) is a key transmitter in motor, reward and cogitative pathways, with DA dysfunction implicated in disorders including Parkinson's disease and addiction. Located in midbrain, DA neurons of the substantia nigra pars compacta project via the medial forebrain bundle to the dorsal striatum (caudate putamen), and DA neurons in the adjacent ventral tegmental area project to the ventral striatum (nucleus accumbens) and prefrontal cortex. In addition to classical vesicular release from axons, midbrain DA neurons exhibit DA release from their cell bodies and dendrites. Somatodendritic DA release leads to activation of D2 DA autoreceptors on DA neurons that inhibit their firing via G-protein-coupled inwardly rectifying K þ channels. This helps determine patterns of DA signalling at distant axonal release sites. Somatodendritically released DA also acts via volume transmission to extrasynaptic receptors that modulate local transmitter release and neuronal activity in the midbrain. Thus, somatodendritic release is a pivotal intrinsic feature of DA neurons that must be well defined in order to fully understand the physiology and pathophysiology of DA pathways. Here, we review recent mechanistic aspects of somatodendritic DA release, with particular emphasis on the Ca 2þ dependence of release and the potential role of exocytotic proteins.

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Spontaneous Inhibitory Synaptic Currents Mediated by a G Protein-Coupled Receptor

Cited by 80 publications

References 31 publications

The Timing of Dopamine- and Noradrenaline-Mediated Transmission Reflects Underlying Differences in the Extent of Spillover and Pooling

The Timing of Dopamine- and Noradrenaline-Mediated Transmission Reflects Underlying Differences in the Extent of Spillover and Pooling

The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants

Somatodendritic dopamine release: recent mechanistic insights

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