Overexpression of the vesicular acetylcholine transporter increased acetylcholine release in the hippocampus

Nagy, Paul Michael; Aubert, Isabelle

doi:10.1016/j.neuroscience.2012.05.047

Cited by 49 publications

(61 citation statements)

References 46 publications

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“…VAChT immunoreactivity was observed in the cell bodies of cholinergic interneurons in both genotypes and in small puncta throughout the striatum, consistent with VAChT function in cell bodies and nerve terminals of cholinergic neurons. Differentially intense VAChT immunoreactive bands were observed at ~70 kDa and ~40 kDa, approximating the size of products that were previously confirmed to be missing in lysates from VAChT knockout mice (Nagy and Aubert, 2012). The intermediate size bands, which were not elevated in the BAC transgenic mice, were presumed to be nonspecific.…”

Section: Resultssupporting

confidence: 74%

“…Consistent with the finding that Slc18a3 transcription is elevated (Kolisnyk et al, 2013b), we observed significantly higher VAChT protein immunolabeling in the striatum and cerebral cortex of hemizygous transgenic mice than in their littermate controls, as determined both by immunoblotting and by immunohistochemistry. Thus, this BAC mouse line is likely to have increased stimulated acetylcholine release in the striatum, based on findings of increased release of acetylcholine in hippocampal slices from this line and a second, similar line (B6.eGFPChAT) (Nagy and Aubert, 2012; Kolisnyk et al, 2013b). VAChT immunoreactivity appeared to be particularly abundant in the lateral striatum, which contains cholinergic interneurons as well as cholinergic afferent fibers from the pedunculopontine nucleus (Dautan et al, 2014), and excitatory inputs from sensorimotor regions of the thalamus (Lanciego et al, 2004) and neocortex (Kincaid and Wilson, 1996).…”

Section: Discussionmentioning

confidence: 96%

“…Moreover, transgenic mouse models that carry multiple copies of Slc18a3 , the gene encoding VAChT, show an increase in evoked release of acetylcholine in hippocampal slices (Nagy and Aubert, 2012; Kolisnyk et al, 2013b). Transgenic mouse and rat lines that are engineered to drive gene expression in cholinergic cells typically carry exogenous copies of the cholinergic gene locus (Eiden, 1998) with an inactivated Chat gene but an intact Slc18a3 gene.…”

Section: Introductionmentioning

confidence: 99%

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Severe drug-induced repetitive behaviors and striatal overexpression of VAChT in ChAT-ChR2-EYFP BAC transgenic mice

Crittenden

Lacey

Lee

et al. 2014

Front. Neural Circuits

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In drug users, drug-related cues alone can induce dopamine release in the dorsal striatum. Instructive cues activate inputs to the striatum from both dopaminergic and cholinergic neurons, which are thought to work together to support motor learning and motivated behaviors. Imbalances in these neuromodulatory influences can impair normal action selection and might thus contribute to pathologically repetitive and compulsive behaviors such as drug addiction. Dopamine and acetylcholine can have either antagonistic or synergistic effects on behavior, depending on the state of the animal and the receptor signaling systems at play. Semi-synchronized activation of cholinergic interneurons in the dorsal striatum drives dopamine release via presynaptic nicotinic acetylcholine receptors located on dopamine terminals. Nicotinic receptor blockade is known to diminish abnormal repetitive behaviors (stereotypies) induced by psychomotor stimulants. By contrast, blockade of postsynaptic acetylcholine muscarinic receptors in the dorsomedial striatum exacerbates drug-induced stereotypy, exemplifying how different acetylcholine receptors can also have opposing effects. Although acetylcholine release is known to be altered in animal models of drug addiction, predicting whether these changes will augment or diminish drug-induced behaviors thus remains a challenge. Here, we measured amphetamine-induced stereotypy in BAC transgenic mice that have been shown to overexpress the vesicular acetylcholine transporter (VAChT) with consequent increased acetylcholine release. We found that drug-induced stereotypies, consisting of confined sniffing and licking behaviors, were greatly increased in the transgenic mice relative to sibling controls, as was striatal VAChT protein. These findings suggest that VAChT-mediated increases in acetylcholine could be critical in exacerbating drug-induced stereotypic behaviors and promoting exaggerated behavioral fixity.

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Section: Resultssupporting

confidence: 74%

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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Severe drug-induced repetitive behaviors and striatal overexpression of VAChT in ChAT-ChR2-EYFP BAC transgenic mice

Crittenden

Lacey

Lee

et al. 2014

Front. Neural Circuits

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“…We present many positive effects of VMAT2 overexpression; however, overexpression of other vesicular transporters has produced mixed results. Vesicular acetylcholine transporter (VAChT) overexpression increases EPSCs in Xenopus (44) and increases acetylcholine release in mouse hippocampal slice (45). ChAT-ChR2-EYFP mice, which also carry several copies of the VAChT gene, show severe cognitive deficits in attention and memory (46).…”

Section: Vmat2-hi Phenotypes Contrast With Vesicular Transporter Overmentioning

confidence: 99%

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.

175

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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“…The relationship between the presence of VAChT and the release of Ach in hippocampal neurons was also described (Nagy and Aubert 2012). The authors Cell Mol Neurobiol demonstrated that the increase in VAChT levels is accompanied by an increase in the release of Ach.…”

Section: Discussionmentioning

confidence: 94%

IL-4 Induces Cholinergic Differentiation of Retinal Cells In Vitro

et al. 2015

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Interleukin-4 (IL-4) is a pleiotropic cytokine that regulates several phenomena, among them survival and differentiation of neuronal and glial cells. The aim of this work was to investigate the effect of IL-4 on the cholinergic differentiation of neonatal rat retinal cells in vitro, evaluating its effect on the levels of cholinergic markers (CHT1-high-affinity choline transporter; VAChT-vesicular acetylcholine transporter, ChAT-choline acetyltransferase, AChE-acetylcholinesterase), muscarinic receptors, and on the signaling pathways involved. Lister Hooded rat pups were used in postnatal days 0-2 (P0-P2). Our results show that IL-4 treatment (50 U/mL) for 48 h increases the levels of the cholinergic transporters VAChT and CHT1, the acetylcholinesterase activity, and the number of ChAT-positive cells. It also induces changes in muscarinic receptor levels, leading to a small decrease in M1 levels and a significant increase in M3 and M5 levels after 48 h of treatment. We also showed that IL-4 effect on M3 receptors is dependent on type I IL-4 receptor and on an increase in NFκB phosphorylation. These results indicate that IL-4 stimulates cholinergic differentiation of retinal cells.

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Overexpression of the vesicular acetylcholine transporter increased acetylcholine release in the hippocampus

Cited by 49 publications

References 46 publications

Severe drug-induced repetitive behaviors and striatal overexpression of VAChT in ChAT-ChR2-EYFP BAC transgenic mice

Severe drug-induced repetitive behaviors and striatal overexpression of VAChT in ChAT-ChR2-EYFP BAC transgenic mice

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

IL-4 Induces Cholinergic Differentiation of Retinal Cells In Vitro

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