The Experts below are selected from a list of 144 Experts worldwide ranked by ideXlab platform
Erwan Bezard - One of the best experts on this subject based on the ideXlab platform.
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Effects of L-tryptophan on L-DOPA-induced dyskinesia in the L-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaque model of Parkinson's disease.
Neuroscience Letters, 2014Co-Authors: Erwan BezardAbstract:In animal models of Parkinson's disease (PD), the serotonergic (5-hydroxytryptamine, 5-HT) system is thought to play an important pathophysiological role in the development and expression of l-3,4-dihydroxyphenylalanine (l-3,4-dihydroxyphenylalanine-DOPA)-induced dyskinesia (LID). These abnormal involuntary movements are associated with the unregulated release of dopamine from 5-HT fibres. Thus, modulating the False Neurotransmitter release from 5-HT neurons, via attuning the serotonin tone, may be a potential therapeutic strategy in the treatment of LID. In this study, we investigated the effects of the primary precursor of 5-HT, l-tryptophan, on LID in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaques. l-tryptophan treatment (0.5-5.0g) dramatically abolished the expression of LID. However, this effect was associated with worsening of the therapeutic effects of L-DOPA. These behavioural data further support the role of the serotonergic system in expression of LID, highlighting the difficult challenge of targeting 5-HT neurons for alleviating dyskinesia and maintaining the therapeutic response of L-DOPA.
Richard J Karpowicz - One of the best experts on this subject based on the ideXlab platform.
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Designing a norepinephrine optical tracer for imaging individual noradrenergic synapses and their activity in vivo.
Nature communications, 2018Co-Authors: Matthew Dunn, Adam Henke, Richard J Karpowicz, David Sulzer, Samuel D. Clark, Yekaterina Kovalyova, Kimberly A. Kempadoo, Eric R. Kandel, Dalibor SamesAbstract:Norepinephrine is a monoamine Neurotransmitter with a wide repertoire of physiological roles in the peripheral and central nervous systems. There are, however, no experimental means to study functional properties of individual noradrenergic synapses in the brain. Development of new approaches for imaging synaptic neurotransmission is of fundamental importance to study specific synaptic changes that occur during learning, behavior, and pathological processes. Here, we introduce fluorescent False Neurotransmitter 270 (FFN270), a fluorescent tracer of norepinephrine. As a fluorescent substrate of the norepinephrine and vesicular monoamine transporters, FFN270 labels noradrenergic neurons and their synaptic vesicles, and enables imaging synaptic vesicle content release from specific axonal sites in living rodents. Combining FFN270 imaging and optogenetic stimulation, we find heterogeneous release properties of noradrenergic synapses in the somatosensory cortex, including low and high releasing populations. Through systemic amphetamine administration, we observe rapid release of cortical noradrenergic vesicular content, providing insight into the drug's effect.
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Designing a norepinephrine optical tracer for imaging individual noradrenergic synapses and their activity in vivo
Nature Communications, 2018Co-Authors: Matthew Dunn, Adam Henke, Richard J Karpowicz, David Sulzer, Yekaterina Kovalyova, Kimberly A. Kempadoo, Eric R. Kandel, Samuel Clark, Dalibor SamesAbstract:Norepinephrine is a monoamine Neurotransmitter with a wide repertoire of physiological roles in the peripheral and central nervous systems. There are, however, no experimental means to study functional properties of individual noradrenergic synapses in the brain. Development of new approaches for imaging synaptic neurotransmission is of fundamental importance to study specific synaptic changes that occur during learning, behavior, and pathological processes. Here, we introduce fluorescent False Neurotransmitter 270 (FFN270), a fluorescent tracer of norepinephrine. As a fluorescent substrate of the norepinephrine and vesicular monoamine transporters, FFN270 labels noradrenergic neurons and their synaptic vesicles, and enables imaging synaptic vesicle content release from specific axonal sites in living rodents. Combining FFN270 imaging and optogenetic stimulation, we find heterogeneous release properties of noradrenergic synapses in the somatosensory cortex, including low and high releasing populations. Through systemic amphetamine administration, we observe rapid release of cortical noradrenergic vesicular content, providing insight into the drug’s effect. The noradrenergic system plays numerous physiological roles but tools to study it are scarce. Here the authors develop a fluorescent analogue of norepinephrine that can be used to label noradrenergic neurons and the synaptic vesicles, and use it to measure single synaptic vesicle release sites in living mice.
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Fluorescent False Neurotransmitter reveals functionally silent dopamine vesicle clusters in the striatum
Nature Neuroscience, 2016Co-Authors: Daniela B Pereira, Yvonne Schmitz, József Mészáros, Paolomi Merchant, Adam Henke, José E Lizardi-ortiz, Richard J Karpowicz, Travis J Morgenstern, Mark S Sonders, Ellen KanterAbstract:The authors report the generation of fluorescent False Neurotransmitter 200 (FFN200), a new optical probe for selectively monitoring monoamine exocytosis in cultured neurons and brain slices. Using the new tool in combination with Ca^2+ imaging, they find functionally silent dopaminergic vesicle clusters in the striatum, with impaired exocytosis at a step downstream from Ca^2+ influx. Neurotransmission at dopaminergic synapses has been studied with techniques that provide high temporal resolution, but cannot resolve individual synapses. To elucidate the spatial dynamics and heterogeneity of individual dopamine boutons, we developed fluorescent False Neurotransmitter 200 (FFN200), a vesicular monoamine transporter 2 (VMAT2) substrate that selectively traces monoamine exocytosis in both neuronal cell culture and brain tissue. By monitoring electrically evoked Ca^2+ transients with GCaMP3 and FFN200 release simultaneously, we found that only a small fraction of dopamine boutons that exhibited Ca^2+ influx engaged in exocytosis, a result confirmed with activity-dependent loading of the endocytic probe FM1-43. Thus, only a low fraction of striatal dopamine axonal sites with uptake-competent VMAT2 vesicles are capable of transmitter release. This is consistent with the presence of functionally 'silent' dopamine vesicle clusters and represents, to the best of our knowledge, the first report suggestive of presynaptically silent neuromodulatory synapses.
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Fluorescent False Neurotransmitter reveals functionally silent dopamine vesicle clusters in the striatum
Nature neuroscience, 2016Co-Authors: Daniela B Pereira, Yvonne Schmitz, József Mészáros, Paolomi Merchant, Adam Henke, José E Lizardi-ortiz, Richard J Karpowicz, Travis J MorgensternAbstract:Neurotransmission at dopaminergic synapses has been studied with techniques that provide high temporal resolution, but cannot resolve individual synapses. To elucidate the spatial dynamics and heterogeneity of individual dopamine boutons, we developed fluorescent False Neurotransmitter 200 (FFN200), a vesicular monoamine transporter 2 (VMAT2) substrate that selectively traces monoamine exocytosis in both neuronal cell culture and brain tissue. By monitoring electrically evoked Ca(2+) transients with GCaMP3 and FFN200 release simultaneously, we found that only a small fraction of dopamine boutons that exhibited Ca(2+) influx engaged in exocytosis, a result confirmed with activity-dependent loading of the endocytic probe FM1-43. Thus, only a low fraction of striatal dopamine axonal sites with uptake-competent VMAT2 vesicles are capable of transmitter release. This is consistent with the presence of functionally 'silent' dopamine vesicle clusters and represents, to the best of our knowledge, the first report suggestive of presynaptically silent neuromodulatory synapses.
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1 APP+, a Fluorescent Analogue of the Neurotoxin MPP+, Is a Marker 2 of Catecholamine Neurons in Brain Tissue, but Not a Fluorescent 3 False Neurotransmitter
2015Co-Authors: Richard J Karpowicz, David Sulzer, Matthew Dunn, Dalibor SamesAbstract:10 ABSTRACT: We have previously introduced fluorescent False 11 Neurotransmitters (FFNs) as optical reporters that enable 12 visualization of individual dopaminergic presynaptic terminals 13 and their activity in the brain. In this context, we examined the 14 fluorescent pyridinium dye 4-(4-dimethylamino)phenyl-1-15 methylpyridinium (APP+), a fluorescent analogue of the 16 dopaminergic neurotoxin MPP+, in acute mouse brain tissue. 17 APP+ is a substrate for the dopamine transporter (DAT), 18 norepinephrine transporter (NET), and serotonin transporter 19 (SERT), and as such represented a candidate for the 20 development of new FFN probes. Here we report that APP 21 + labels cell bodies of catecholaminergic neurons in the 22 midbrain in a DAT- and NET-dependent manner, as well as fine dopaminergic axonal processes in the dorsal striatum. APP+ 23 destaining from presynaptic terminals in the dorsal striatum was also examined under the conditions inducing depolarization and 24 exocytotic Neurotransmitter release. Application of a high concentration of KCl led to a small but significant degree of destainin
Dalibor Sames - One of the best experts on this subject based on the ideXlab platform.
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Evoked transients of pH-sensitive fluorescent False Neurotransmitter reveal dopamine hot spots in the globus pallidus.
eLife, 2018Co-Authors: József Mészáros, Timothy Cheung, Maya M Erler, Un Jung Kang, Dalibor Sames, Christoph Kellendonk, David SulzerAbstract:Dopamine neurotransmission is suspected to play important physiological roles in multiple sparsely innervated brain nuclei, but there has not been a means to measure synaptic dopamine release in such regions. The globus pallidus externa (GPe) is a major locus in the basal ganglia that displays a sparse innervation of en passant dopamine axonal fibers. Due to the low levels of innervation that preclude electrochemical analysis, it is unknown if these axons engage in neurotransmission. To address this, we introduce an optical approach using a pH-sensitive fluorescent False Neurotransmitter, FFN102, that exhibits increased fluorescence upon exocytosis from the acidic synaptic vesicle to the neutral extracellular milieu. In marked contrast to the striatum, FFN102 transients in the mouse GPe were spatially heterogeneous and smaller than in striatum with the exception of sparse hot spots. GPe transients were also significantly enhanced by high frequency stimulation. Our results support hot spots of dopamine release from substantia nigra axons.
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Designing a norepinephrine optical tracer for imaging individual noradrenergic synapses and their activity in vivo.
Nature communications, 2018Co-Authors: Matthew Dunn, Adam Henke, Richard J Karpowicz, David Sulzer, Samuel D. Clark, Yekaterina Kovalyova, Kimberly A. Kempadoo, Eric R. Kandel, Dalibor SamesAbstract:Norepinephrine is a monoamine Neurotransmitter with a wide repertoire of physiological roles in the peripheral and central nervous systems. There are, however, no experimental means to study functional properties of individual noradrenergic synapses in the brain. Development of new approaches for imaging synaptic neurotransmission is of fundamental importance to study specific synaptic changes that occur during learning, behavior, and pathological processes. Here, we introduce fluorescent False Neurotransmitter 270 (FFN270), a fluorescent tracer of norepinephrine. As a fluorescent substrate of the norepinephrine and vesicular monoamine transporters, FFN270 labels noradrenergic neurons and their synaptic vesicles, and enables imaging synaptic vesicle content release from specific axonal sites in living rodents. Combining FFN270 imaging and optogenetic stimulation, we find heterogeneous release properties of noradrenergic synapses in the somatosensory cortex, including low and high releasing populations. Through systemic amphetamine administration, we observe rapid release of cortical noradrenergic vesicular content, providing insight into the drug's effect.
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Designing a norepinephrine optical tracer for imaging individual noradrenergic synapses and their activity in vivo
Nature Communications, 2018Co-Authors: Matthew Dunn, Adam Henke, Richard J Karpowicz, David Sulzer, Yekaterina Kovalyova, Kimberly A. Kempadoo, Eric R. Kandel, Samuel Clark, Dalibor SamesAbstract:Norepinephrine is a monoamine Neurotransmitter with a wide repertoire of physiological roles in the peripheral and central nervous systems. There are, however, no experimental means to study functional properties of individual noradrenergic synapses in the brain. Development of new approaches for imaging synaptic neurotransmission is of fundamental importance to study specific synaptic changes that occur during learning, behavior, and pathological processes. Here, we introduce fluorescent False Neurotransmitter 270 (FFN270), a fluorescent tracer of norepinephrine. As a fluorescent substrate of the norepinephrine and vesicular monoamine transporters, FFN270 labels noradrenergic neurons and their synaptic vesicles, and enables imaging synaptic vesicle content release from specific axonal sites in living rodents. Combining FFN270 imaging and optogenetic stimulation, we find heterogeneous release properties of noradrenergic synapses in the somatosensory cortex, including low and high releasing populations. Through systemic amphetamine administration, we observe rapid release of cortical noradrenergic vesicular content, providing insight into the drug’s effect. The noradrenergic system plays numerous physiological roles but tools to study it are scarce. Here the authors develop a fluorescent analogue of norepinephrine that can be used to label noradrenergic neurons and the synaptic vesicles, and use it to measure single synaptic vesicle release sites in living mice.
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1 APP+, a Fluorescent Analogue of the Neurotoxin MPP+, Is a Marker 2 of Catecholamine Neurons in Brain Tissue, but Not a Fluorescent 3 False Neurotransmitter
2015Co-Authors: Richard J Karpowicz, David Sulzer, Matthew Dunn, Dalibor SamesAbstract:10 ABSTRACT: We have previously introduced fluorescent False 11 Neurotransmitters (FFNs) as optical reporters that enable 12 visualization of individual dopaminergic presynaptic terminals 13 and their activity in the brain. In this context, we examined the 14 fluorescent pyridinium dye 4-(4-dimethylamino)phenyl-1-15 methylpyridinium (APP+), a fluorescent analogue of the 16 dopaminergic neurotoxin MPP+, in acute mouse brain tissue. 17 APP+ is a substrate for the dopamine transporter (DAT), 18 norepinephrine transporter (NET), and serotonin transporter 19 (SERT), and as such represented a candidate for the 20 development of new FFN probes. Here we report that APP 21 + labels cell bodies of catecholaminergic neurons in the 22 midbrain in a DAT- and NET-dependent manner, as well as fine dopaminergic axonal processes in the dorsal striatum. APP+ 23 destaining from presynaptic terminals in the dorsal striatum was also examined under the conditions inducing depolarization and 24 exocytotic Neurotransmitter release. Application of a high concentration of KCl led to a small but significant degree of destainin
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APP+, a fluorescent analogue of the neurotoxin MPP+, is a marker of catecholamine neurons in brain tissue, but not a fluorescent False Neurotransmitter.
ACS chemical neuroscience, 2013Co-Authors: Richard J Karpowicz, David Sulzer, Matthew Dunn, Dalibor SamesAbstract:We have previously introduced fluorescent False Neurotransmitters (FFNs) as optical reporters that enable visualization of individual dopaminergic presynaptic terminals and their activity in the brain. In this context, we examined the fluorescent pyridinium dye 4-(4-dimethylamino)phenyl-1-methylpyridinium (APP+), a fluorescent analogue of the dopaminergic neurotoxin MPP+, in acute mouse brain tissue. APP+ is a substrate for the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT), and as such represented a candidate for the development of new FFN probes. Here we report that APP+ labels cell bodies of catecholaminergic neurons in the midbrain in a DAT- and NET-dependent manner, as well as fine dopaminergic axonal processes in the dorsal striatum. APP+ destaining from presynaptic terminals in the dorsal striatum was also examined under the conditions inducing depolarization and exocytotic Neurotransmitter release. Application of KCl led to a small but significant de...
Adam Henke - One of the best experts on this subject based on the ideXlab platform.
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Designing a norepinephrine optical tracer for imaging individual noradrenergic synapses and their activity in vivo.
Nature communications, 2018Co-Authors: Matthew Dunn, Adam Henke, Richard J Karpowicz, David Sulzer, Samuel D. Clark, Yekaterina Kovalyova, Kimberly A. Kempadoo, Eric R. Kandel, Dalibor SamesAbstract:Norepinephrine is a monoamine Neurotransmitter with a wide repertoire of physiological roles in the peripheral and central nervous systems. There are, however, no experimental means to study functional properties of individual noradrenergic synapses in the brain. Development of new approaches for imaging synaptic neurotransmission is of fundamental importance to study specific synaptic changes that occur during learning, behavior, and pathological processes. Here, we introduce fluorescent False Neurotransmitter 270 (FFN270), a fluorescent tracer of norepinephrine. As a fluorescent substrate of the norepinephrine and vesicular monoamine transporters, FFN270 labels noradrenergic neurons and their synaptic vesicles, and enables imaging synaptic vesicle content release from specific axonal sites in living rodents. Combining FFN270 imaging and optogenetic stimulation, we find heterogeneous release properties of noradrenergic synapses in the somatosensory cortex, including low and high releasing populations. Through systemic amphetamine administration, we observe rapid release of cortical noradrenergic vesicular content, providing insight into the drug's effect.
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Designing a norepinephrine optical tracer for imaging individual noradrenergic synapses and their activity in vivo
Nature Communications, 2018Co-Authors: Matthew Dunn, Adam Henke, Richard J Karpowicz, David Sulzer, Yekaterina Kovalyova, Kimberly A. Kempadoo, Eric R. Kandel, Samuel Clark, Dalibor SamesAbstract:Norepinephrine is a monoamine Neurotransmitter with a wide repertoire of physiological roles in the peripheral and central nervous systems. There are, however, no experimental means to study functional properties of individual noradrenergic synapses in the brain. Development of new approaches for imaging synaptic neurotransmission is of fundamental importance to study specific synaptic changes that occur during learning, behavior, and pathological processes. Here, we introduce fluorescent False Neurotransmitter 270 (FFN270), a fluorescent tracer of norepinephrine. As a fluorescent substrate of the norepinephrine and vesicular monoamine transporters, FFN270 labels noradrenergic neurons and their synaptic vesicles, and enables imaging synaptic vesicle content release from specific axonal sites in living rodents. Combining FFN270 imaging and optogenetic stimulation, we find heterogeneous release properties of noradrenergic synapses in the somatosensory cortex, including low and high releasing populations. Through systemic amphetamine administration, we observe rapid release of cortical noradrenergic vesicular content, providing insight into the drug’s effect. The noradrenergic system plays numerous physiological roles but tools to study it are scarce. Here the authors develop a fluorescent analogue of norepinephrine that can be used to label noradrenergic neurons and the synaptic vesicles, and use it to measure single synaptic vesicle release sites in living mice.
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Fluorescent False Neurotransmitter reveals functionally silent dopamine vesicle clusters in the striatum
Nature Neuroscience, 2016Co-Authors: Daniela B Pereira, Yvonne Schmitz, József Mészáros, Paolomi Merchant, Adam Henke, José E Lizardi-ortiz, Richard J Karpowicz, Travis J Morgenstern, Mark S Sonders, Ellen KanterAbstract:The authors report the generation of fluorescent False Neurotransmitter 200 (FFN200), a new optical probe for selectively monitoring monoamine exocytosis in cultured neurons and brain slices. Using the new tool in combination with Ca^2+ imaging, they find functionally silent dopaminergic vesicle clusters in the striatum, with impaired exocytosis at a step downstream from Ca^2+ influx. Neurotransmission at dopaminergic synapses has been studied with techniques that provide high temporal resolution, but cannot resolve individual synapses. To elucidate the spatial dynamics and heterogeneity of individual dopamine boutons, we developed fluorescent False Neurotransmitter 200 (FFN200), a vesicular monoamine transporter 2 (VMAT2) substrate that selectively traces monoamine exocytosis in both neuronal cell culture and brain tissue. By monitoring electrically evoked Ca^2+ transients with GCaMP3 and FFN200 release simultaneously, we found that only a small fraction of dopamine boutons that exhibited Ca^2+ influx engaged in exocytosis, a result confirmed with activity-dependent loading of the endocytic probe FM1-43. Thus, only a low fraction of striatal dopamine axonal sites with uptake-competent VMAT2 vesicles are capable of transmitter release. This is consistent with the presence of functionally 'silent' dopamine vesicle clusters and represents, to the best of our knowledge, the first report suggestive of presynaptically silent neuromodulatory synapses.
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Fluorescent False Neurotransmitter reveals functionally silent dopamine vesicle clusters in the striatum
Nature neuroscience, 2016Co-Authors: Daniela B Pereira, Yvonne Schmitz, József Mészáros, Paolomi Merchant, Adam Henke, José E Lizardi-ortiz, Richard J Karpowicz, Travis J MorgensternAbstract:Neurotransmission at dopaminergic synapses has been studied with techniques that provide high temporal resolution, but cannot resolve individual synapses. To elucidate the spatial dynamics and heterogeneity of individual dopamine boutons, we developed fluorescent False Neurotransmitter 200 (FFN200), a vesicular monoamine transporter 2 (VMAT2) substrate that selectively traces monoamine exocytosis in both neuronal cell culture and brain tissue. By monitoring electrically evoked Ca(2+) transients with GCaMP3 and FFN200 release simultaneously, we found that only a small fraction of dopamine boutons that exhibited Ca(2+) influx engaged in exocytosis, a result confirmed with activity-dependent loading of the endocytic probe FM1-43. Thus, only a low fraction of striatal dopamine axonal sites with uptake-competent VMAT2 vesicles are capable of transmitter release. This is consistent with the presence of functionally 'silent' dopamine vesicle clusters and represents, to the best of our knowledge, the first report suggestive of presynaptically silent neuromodulatory synapses.
József Mészáros - One of the best experts on this subject based on the ideXlab platform.
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Evoked transients of pH-sensitive fluorescent False Neurotransmitter reveal dopamine hot spots in the globus pallidus.
eLife, 2018Co-Authors: József Mészáros, Timothy Cheung, Maya M Erler, Un Jung Kang, Dalibor Sames, Christoph Kellendonk, David SulzerAbstract:Dopamine neurotransmission is suspected to play important physiological roles in multiple sparsely innervated brain nuclei, but there has not been a means to measure synaptic dopamine release in such regions. The globus pallidus externa (GPe) is a major locus in the basal ganglia that displays a sparse innervation of en passant dopamine axonal fibers. Due to the low levels of innervation that preclude electrochemical analysis, it is unknown if these axons engage in neurotransmission. To address this, we introduce an optical approach using a pH-sensitive fluorescent False Neurotransmitter, FFN102, that exhibits increased fluorescence upon exocytosis from the acidic synaptic vesicle to the neutral extracellular milieu. In marked contrast to the striatum, FFN102 transients in the mouse GPe were spatially heterogeneous and smaller than in striatum with the exception of sparse hot spots. GPe transients were also significantly enhanced by high frequency stimulation. Our results support hot spots of dopamine release from substantia nigra axons.
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Fluorescent False Neurotransmitter reveals functionally silent dopamine vesicle clusters in the striatum
Nature Neuroscience, 2016Co-Authors: Daniela B Pereira, Yvonne Schmitz, József Mészáros, Paolomi Merchant, Adam Henke, José E Lizardi-ortiz, Richard J Karpowicz, Travis J Morgenstern, Mark S Sonders, Ellen KanterAbstract:The authors report the generation of fluorescent False Neurotransmitter 200 (FFN200), a new optical probe for selectively monitoring monoamine exocytosis in cultured neurons and brain slices. Using the new tool in combination with Ca^2+ imaging, they find functionally silent dopaminergic vesicle clusters in the striatum, with impaired exocytosis at a step downstream from Ca^2+ influx. Neurotransmission at dopaminergic synapses has been studied with techniques that provide high temporal resolution, but cannot resolve individual synapses. To elucidate the spatial dynamics and heterogeneity of individual dopamine boutons, we developed fluorescent False Neurotransmitter 200 (FFN200), a vesicular monoamine transporter 2 (VMAT2) substrate that selectively traces monoamine exocytosis in both neuronal cell culture and brain tissue. By monitoring electrically evoked Ca^2+ transients with GCaMP3 and FFN200 release simultaneously, we found that only a small fraction of dopamine boutons that exhibited Ca^2+ influx engaged in exocytosis, a result confirmed with activity-dependent loading of the endocytic probe FM1-43. Thus, only a low fraction of striatal dopamine axonal sites with uptake-competent VMAT2 vesicles are capable of transmitter release. This is consistent with the presence of functionally 'silent' dopamine vesicle clusters and represents, to the best of our knowledge, the first report suggestive of presynaptically silent neuromodulatory synapses.
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Fluorescent False Neurotransmitter reveals functionally silent dopamine vesicle clusters in the striatum
Nature neuroscience, 2016Co-Authors: Daniela B Pereira, Yvonne Schmitz, József Mészáros, Paolomi Merchant, Adam Henke, José E Lizardi-ortiz, Richard J Karpowicz, Travis J MorgensternAbstract:Neurotransmission at dopaminergic synapses has been studied with techniques that provide high temporal resolution, but cannot resolve individual synapses. To elucidate the spatial dynamics and heterogeneity of individual dopamine boutons, we developed fluorescent False Neurotransmitter 200 (FFN200), a vesicular monoamine transporter 2 (VMAT2) substrate that selectively traces monoamine exocytosis in both neuronal cell culture and brain tissue. By monitoring electrically evoked Ca(2+) transients with GCaMP3 and FFN200 release simultaneously, we found that only a small fraction of dopamine boutons that exhibited Ca(2+) influx engaged in exocytosis, a result confirmed with activity-dependent loading of the endocytic probe FM1-43. Thus, only a low fraction of striatal dopamine axonal sites with uptake-competent VMAT2 vesicles are capable of transmitter release. This is consistent with the presence of functionally 'silent' dopamine vesicle clusters and represents, to the best of our knowledge, the first report suggestive of presynaptically silent neuromodulatory synapses.