<i>Vmat2</i>Heterozygous Mutant Mice Display a Depressive-Like Phenotype

Fukui, Masato; Rodriguiz, Ramona M.; Zhou, Jiechun; Jiang, Xiaoyin “Sara”; Phillips, Lindsey E.; Caron, Marc G.; Wetsel, William C.

doi:10.1523/jneurosci.4388-06.2007

Cited by 136 publications

(160 citation statements)

References 74 publications

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“…The absence of increased anxiety in VMAT2-HET constitutive mice 14 was reproduced in our conditional models. These results are similar to those of hypertensive patients treated with the VMAT2 blocker reserpine in whom anxiety did not appear to accompany a depressive state.…”

Section: Altering 1 Monoaminergic System Is Not Sufficient To Induce mentioning

confidence: 71%

“…40 Although they are often comorbid, anxiety and depression are 2 independent affective-related disorders. A depressive-like phenotype without changes in anxiety level has been observed in VMAT2-HET mice, 14 and this particular trait could not be observed in any of the specific mice we engineered. The sucrose preference and CPP alteration in VMAT2-HET mice was not replicated in our conditional models, suggesting that the alteration of only 1 monoamine system is not sufficient to induce anhedonic behaviour.…”

Section: Altering 1 Monoaminergic System Is Not Sufficient To Induce mentioning

confidence: 75%

“…12,13 The behavioural characterization of VMAT2-HET and WT animals did not indicate any difference in anxiety levels, although a sucrose preference test revealed that HET mice are less responsive to sucrose. 14 In conjunction with the decreased CPP in HET mice, these data suggest the presence of anhedonia in VMAT2-HET mice.…”

Section: J Psychiatry Neurosci 2016;41(3)mentioning

confidence: 77%

“…The levels of NE, 5-HT and DA are decreased by 94%-99% in the neonatal VMAT2-KO brain and by 34%, 23% and 42%, respectively, in VMAT2-HET mice. Behaviourally, spontaneous locomotor activity and rearing are decreased in VMAT2-HET mice compared with their wild-type (WT) littermates; 14 however, VMAT2-HET mice are more active under the effects of cocaine and amphetamine in the open-field test. This increased locomotor response to drugs is associated with a decreased sensitization to cocaine and a reduction in amphetamine-conditioned place preference (CPP).…”

Section: J Psychiatry Neurosci 2016;41(3)mentioning

confidence: 99%

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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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Section: Altering 1 Monoaminergic System Is Not Sufficient To Induce mentioning

confidence: 71%

Section: Altering 1 Monoaminergic System Is Not Sufficient To Induce mentioning

confidence: 75%

Section: J Psychiatry Neurosci 2016;41(3)mentioning

confidence: 77%

Section: J Psychiatry Neurosci 2016;41(3)mentioning

confidence: 99%

See 2 more Smart Citations

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

Isingrini¹,

Perret²,

Rainer³

et al. 2016

jpn

View full text Add to dashboard Cite

show abstract

“…In addition, repeatedly exposing rats to immobilization or forced swimming has been found to increase or decrease VMAT2 expression (Rusnak et al, 2001;Zucker et al, 2005). Beyond these data there is still surprisingly little investigation of VMAT2's possible role in modulating the stress response until a recent report in a mouse model of loss of Vmat2 (Slc18a2) gene function (Fukui et al, 2007).…”

Section: Serotonin Vesicular Packagingmentioning

confidence: 99%

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

Holmes

2008

Neuroscience & Biobehavioral Reviews

249

166

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The serotonin system is strongly implicated in the pathophysiology and therapeutic alleviation of stress-related disorders such as anxiety and depression. Serotonergic modulation of the acute response to stress and the adaptation to chronic stress is mediated by a myriad of molecules controlling serotonin neuron development (Pet-1), synthesis (tryptophan hydroxylase 1 and 2 isozymes), packaging (vesicular monoamine transporter 2), actions at presynaptic and postsynaptic receptors (5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT3A, 5-HT4, 5-HT5A, 5-HT6, 5-HT7), reuptake (serotonin transporter), and degradation (monoamine oxidase A). A growing body of evidence from preclinical rodents models, and especially genetically modified mice and inbred mouse strains, has provided significant insight into how genetic variation in these molecules can affect the development and function of a key neural circuit between the dorsal raphe nucleus, medial prefrontal cortex and amygdala. By extension, such variation is hypothesized to have a major influence on individual differences in the stress response and risk for stress-related disease in humans. The current article provides an update on this rapidly evolving field of research.

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Altered expression of vesicular monoamine transporter 2 in epileptic patients and experimental rats

Jiang

Cao

et al. 2013

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In the central nervous system (CNS), vesicular monoamine transporter 2 (VMAT2) transports cytoplasmic monoamines such as dopamine into synaptic vesicles for storage and subsequent exocytotic release. Recent studies have provided direct evidence for VMAT2-regulated monoamine neurotransmitter involvement in the neurophysiological activities of neurological disease. This study investigated the expression pattern of VMAT2 in patients with temporal lobe epilepsy (TLE) and in a rat model of epilepsy. We assessed the expression of VMAT2 in the temporal neocortex in 24 TLE patients using western blotting and quantitative real time PCR (qRT-PCR) analyses. These results showed that VMAT2 expression dynamically decreased in TLE patients when compared with the control subjects (n = 12). And that VMAT2 protein transiently increased in acute stages (1 day and 3 days) after epileptic seizures in pilocarpine-treated rats; however, it clearly decreased after spontaneous recurrent seizures (7 days, 21 days, and 60 days after seizures). In addition, double immunofluorescence and immunohistochemical labeling studies performed in patient and experimental animal tissue revealed that VMAT2 protein was mainly expressed in the cytoplasm and in the axons of neurons but not glial cells in the hippocampus and temporal lobe cortex. These data suggested that the abnormal expression of VMAT2 mRNA and protein in epileptic brain tissue may contribute to vulnerability toward epilepsy-related psychiatric disorders and cognitive impairment.

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Vmat2Heterozygous Mutant Mice Display a Depressive-Like Phenotype

Cited by 136 publications

References 74 publications

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

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

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

Altered expression of vesicular monoamine transporter 2 in epileptic patients and experimental rats

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