Synaptic Vesicle Transporter Expression Regulates Vesicle Phenotype and Quantal Size

Pothos, Emmanuel N.; Larsen, Kristin E.; Krantz, David E.; Liu, Yongjian; Haycock, John W.; Setlik, Wanda; Gershon, Michael D.; Edwards, Robert H.; Sulzer, David

doi:10.1523/jneurosci.20-19-07297.2000

Cited by 189 publications

(155 citation statements)

References 50 publications

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“…In this scenario, the amount of VMAT2 would have no effect on vesicle content. However, in vitro work has shown in both chromaffin cells and dopamine neurons that VMAT2 overexpression alters quantal size independent of activity (i.e., regardless of the speed of vesicle recycling) (37). Recent evidence, including the in vivo results presented here with the VMAT2-HI mice, suggests that membrane equilibrium is not a limiting factor to monoamine vesicle filling (37)(38)(39).…”

Section: Vmat2-hi Mice Reveal An Unexpected Enhancement Of Vesicular mentioning

confidence: 65%

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Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo

Lohr¹,

Bernstein²,

Stout³

et al. 2014

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

167

171

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Significance Several therapeutic strategies have been used to enhance monoamine neurotransmitter signaling. However, many of these interventions have deleterious side effects or lose effectiveness due to off-target actions and system feedback. These undesirable consequences likely occur because of temporal dysregulation of neurotransmitter release and uptake. We demonstrate that increasing vesicular packaging enhances dopamine neurotransmission without this signaling disruption. Mice with elevated vesicular monoamine transporter display increased dopamine release, improved outcomes on anxiety and depressive behaviors, enhanced locomotion, and protection from a Parkinson disease-related neurotoxic insult. The malleable nature of the dopamine vesicle suggests that interventions aimed at enhancing vesicle filling may be of therapeutic benefit.

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Section: Vmat2-hi Mice Reveal An Unexpected Enhancement Of Vesicular mentioning

confidence: 65%

“…Overexpression of VMAT2 has been shown to increase dopamine release by increasing quantal size in both chromaffin cells and primary midbrain culture (37,38). Similarly, VMAT2-HI mice show an 84% increase in stimulated striatal dopamine release (Fig.…”

Section: Vmat2 Overexpression Increases Dopamine Release and Neurotramentioning

confidence: 82%

Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo

Lohr¹,

Bernstein²,

Stout³

et al. 2014

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

167

171

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“…VMAT2 is an essential regulator of the quantal size of neurotransmitter release, 11,36 and its downregulation by 50% induced a strong phenotype in the constitutive . However, although locomotor sensitization was observed in the WT mice of the VMAT2 SERTcre line (middle), no sensitization appeared in the HET mice (WT mice, n = 9, HET mice, n = 8).…”

Section: Discussionmentioning

confidence: 99%

Selective genetic disruption of dopaminergic, serotonergic and noradrenergic neurotransmission: insights into motor, emotional and addictive behaviour

Isingrini¹,

Perret²,

Rainer³

et al. 2016

jpn

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IntroductionMonoaminergic neurotransmitters, namely dopamine (DA), noradrenaline (NE) and serotonin (5-HT), extensively modulate cognitive, affective, neuroendocrine and motor functions in the brain. 1 The role of the monoaminergic systems in psychi atric pathology has been clearly established based on the observation that effective psychotropic drugs primarily target these systems. [2][3][4] However, the functional subdivision of the monoamine systems indicates a disparity in cerebral distribution, receptor subtypes and mechanisms of action. Unravelling the independent roles of the monoaminergic systems in patients with neuropsychiatric disorders remains a challenge that is complicated by their large anatomic, pharmacological and functional overlaps.At the molecular level, the monoaminergic systems share common properties. The intra-and extracellular concentrations of monoamines are primarily controlled by 2 types of transporters. The plasma membrane transporters (norepinephrine transporter [NET], serotonin transporter [SERT] and dopamine transporter [DAT]) play an essential role in the clearance and recycling of monoamines via uptake from the extracellular space, and the vesicular monoamine transporter (VMAT) accumulates monoamines in synaptic vesicles and is essential for their release. 5 Two VMAT genes have been cloned, 6,7 and although the proteins encoded by these genes are structurally related, they fulfill distinct roles. VMAT1 is primarily expressed in the peripheral nervous system; VMAT2 is primarily expressed in the neurons of the central nervous system. 8,9 The functions of VMAT2 include storage of monoamines, protection of monoamines from cytoplasmic oxi dation and regulation of stimulated monoamine quantal release. 10 Thus, VMAT2 deficiency contributes to a decrease in the synaptic release of monoamines and an increase in the degradation of intracellular monoamines.To better understand the physiologic and behavioural roles of monoaminergic signalling, several investigators have created VMAT2-knockout (KO) mice by disrupting the gene that Background:The monoaminergic transmitters dopamine (DA), noradrenaline (NE) and serotonin (5-HT) modulate cerebral functions via their extensive effects in the brain. Investigating their roles has led to the creation of vesicular monoaminergic transporter-2 (VMAT2) knockout (KO) mice. While this mutation results in postnatal death, VMAT2-heterozygous (HET) mice are viable and show a complex behavioural phenotype. However, the simultaneous alteration of the 3 systems prevents investigations into their individual functions. Methods: To assess the specific role of NE, 5-HT and DA, we genetically disrupted their neurotransmission by creating conditional VMAT2-KO mice with targeted recombination. These specific recombinations were obtained by breeding VMAT2 lox/lox mice with DBHcre, SERTcre and DATcre mice, respectively. We conducted a complete neurochemical and behavioural characterization of VMAT2-HET animals in each system. Results: Conditional VMAT2-KO mice reveale...

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“…At the frog neuromuscular junction, the vesicular acetylcholine transporter expression level seems to be the limiting factor for cholinergic quantal size (38), and the same appears to be true for vesicular packaging of monoamines, which is enhanced by vesicular monoamine transporter 2 overexpression in PC12 cells and ventral midbrain neurons, whereas total monoamine stores are reduced in the brains of vesicular monoamine transporter 2 ϩ͞Ϫ mice (39)(40)(41). In vivo, demands made on the vesicular filling rate are likely to differ between vesicular acetylcholine transporter, vesicular monoamine transporter, and VGLUT, and they might be particularly high for VGLUT.…”

Section: Discussionmentioning

confidence: 99%

An essential role for vesicular glutamate transporter 1 (VGLUT1) in postnatal development and control of quantal size

Wojcik

Rhee

Herzog

et al. 2004

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

439

447

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Quantal neurotransmitter release at excitatory synapses depends on glutamate import into synaptic vesicles by vesicular glutamate transporters (VGLUTs). Of the three known transporters, VGLUT1 and VGLUT2 are expressed prominently in the adult brain, but during the first two weeks of postnatal development, VGLUT2 expression predominates. Targeted deletion of VGLUT1 in mice causes lethality in the third postnatal week. Glutamatergic neurotransmission is drastically reduced in neurons from VGLUT1-deficient mice, with a specific reduction in quantal size. The remaining activity correlates with the expression of VGLUT2. This reduction in glutamatergic neurotransmission can be rescued and enhanced with overexpression of VGLUT1. These results show that the expression level of VGLUTs determines the amount of glutamate that is loaded into vesicles and released and thereby regulates the efficacy of neurotransmission.

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Synaptic Vesicle Transporter Expression Regulates Vesicle Phenotype and Quantal Size

Cited by 189 publications

References 50 publications

Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo

Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo

Selective genetic disruption of dopaminergic, serotonergic and noradrenergic neurotransmission: insights into motor, emotional and addictive behaviour

An essential role for vesicular glutamate transporter 1 (VGLUT1) in postnatal development and control of quantal size

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