Sub-regional differences and mechanisms of the short-term plasticity of dopamine overflow in striatum in mice lacking alpha-synuclein

Chadchankar, Heramb; Yavich, Leonid

doi:10.1016/j.brainres.2011.09.026

Cited by 18 publications

(11 citation statements)

References 42 publications

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“…Our finding of differences in the short‐term plasticity of evoked DA release in the dorsal striatum and NAcc is consistent with the previous reports of Cragg () and of Chadchankar & Yavich (). Cragg () reported short‐term depression in tissue slices from the dorsal part of the primate striatum (putamen) and short‐term facilitation in the nucleus accumbens.…”

Section: Discussionsupporting

confidence: 93%

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The dopamine patchwork of the rat nucleus accumbens core

Zhan

Taylor

Michael

2013

Eur J of Neuroscience

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The dopamine (DA) terminal field in rat dorsal striatum is organized as a patchwork of domains that exhibit distinct DA kinetics. The rate and short-term plasticity of evoked DA release, the rate of DA clearance, and the actions of several dopaminergic drugs are all domain-dependent. The patchwork arises in part from local variations in DA’s basal extracellular concentration, which establishes an autoinhibitory tone in slow but not fast domains. The present study addressed the hypothesis that a domain patchwork might also exist in the nucleus accumbens core (NAcc), a DA terminal field involved deeply in reward processing and the mechanisms underlying substance abuse. DA recordings in the NAcc by fast-scan voltammetry during electrical stimulation of the medial forebrain bundle confirm that the NAcc contains a patchwork of fast and slow domains exhibiting significantly different rates of evoked DA release and DA clearance. Moreover, the NAcc domains are substantially different from those in the dorsal striatum. There are no signs in the NAcc of short-term plasticity of DA release during multiple consecutive stimuli and no signs of a domain-dependent autoinhibitory tone. Thus, the NAcc domains are distinct from each other and from the domains of the dorsal striatum.

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Section: Discussionsupporting

confidence: 93%

“…Cragg () reported short‐term depression in tissue slices from the dorsal part of the primate striatum (putamen) and short‐term facilitation in the nucleus accumbens. Using a different stimulus protocol, Chadchankar & Yavich () reported short‐term facilitation in the dorsal but not the ventral striatum of the mouse.…”

Section: Discussionmentioning

confidence: 99%

The dopamine patchwork of the rat nucleus accumbens core

Zhan

Taylor

Michael

2013

Eur J of Neuroscience

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“…The original study reporting a knockout of α‐synuclein showed no effect on excitatory neurotransmission, a slight reduction in dopamine levels, and faster recovery of dopamine release from paired pulse stimulation in striatal slices (Abeliovich et al ), suggesting a selective inhibitory effect on the pre‐synaptic recovery of dopamine release. The spontaneous deletion of α‐synuclein and an adjacent gene in C57Bl/6OlaHsd mice produce a very similar phenotype (Chadchankar and Yavich ). Importantly, the loss of α‐synuclein has only a modest effect on behavior – reduced locomotor response to psychostimulants, consistent with reduced dopamine stores (Abeliovich et al ), but increased intracranial self‐stimulation (Oksman et al ).…”

Section: The Function Of α‐Synucleinmentioning

confidence: 99%

The physiological role of α‐synuclein and its relationship to Parkinson’s Disease

Sulzer

Edwards²

2019

Journal of Neurochemistry

242

187

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The protein α‐synuclein has a central role in the pathogenesis of Parkinson’s disease (PD). In this review, we discuss recent results concerning its primary function, which appears to be on cell membranes. The pre‐synaptic location of synuclein has suggested a role in neurotransmitter release and it apparently associates with synaptic vesicles because of their high curvature. Indeed, synuclein over‐expression inhibits synaptic vesicle exocytosis. However, loss of synuclein has not yet been shown to have a major effect on synaptic transmission. Consistent with work showing that synuclein can promote as well as sense membrane curvature, recent analysis of synuclein triple knockout mice now shows that synuclein accelerates dilation of the exocytic fusion pore. This form of regulation affects primarily the release of slowly discharged lumenal cargo such as neural peptides, but presumably also contributes to maintenance of the release site. This article is part of the Special Issue “Synuclein”.

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“…[19][20][21][22] Further, alterations in synaptic transmission have been found in mice overexpressing or down-expressing a-synuclein. [23][24][25][26][27][28][29][30][31][32][33][34][35] Despite this, it is still unclear how a-synuclein contributes to early functional changes and cell death in PD, and potential strategies to either reduce the basal levels of a-synuclein or to inhibit its process of aggregation are being explored. Preclinical studies have successfully shown a-synuclein downregulation both in cell culture and animal models using antisense oligonucleotides (ASOs), ribozymes, small interfering RNAs (siRNAs), or microRNA without neurotoxic effects.…”

Section: Introductionmentioning

confidence: 99%

Selective α-Synuclein Knockdown in Monoamine Neurons by Intranasal Oligonucleotide Delivery: Potential Therapy for Parkinson’s Disease

et al. 2018

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Progressive neuronal death in brainstem nuclei and widespread accumulation of α-synuclein are neuropathological hallmarks of Parkinson's disease (PD). Reduction of α-synuclein levels is therefore a potential therapy for PD. However, because α-synuclein is essential for neuronal development and function, α-synuclein elimination would dramatically impact brain function. We previously developed conjugated small interfering RNA (siRNA) sequences that selectively target serotonin (5-HT) or norepinephrine (NE) neurons after intranasal administration. Here, we used this strategy to conjugate inhibitory oligonucleotides, siRNA and antisense oligonucleotide (ASO), with the triple monoamine reuptake inhibitor indatraline (IND), to selectively reduce α-synuclein expression in the brainstem monoamine nuclei of mice after intranasal delivery. Following internalization of the conjugated oligonucleotides in monoamine neurons, reduced levels of endogenous α-synuclein mRNA and protein were found in substantia nigra pars compacta (SNc), ventral tegmental area (VTA), dorsal raphe nucleus (DR), and locus coeruleus (LC). α-Synuclein knockdown by ∼20%-40% did not cause monoaminergic neurodegeneration and enhanced forebrain dopamine (DA) and 5-HT release. Conversely, a modest human α-synuclein overexpression in DA neurons markedly reduced striatal DA release. These results indicate that α-synuclein negatively regulates monoamine neurotransmission and set the stage for the testing of non-viral inhibitory oligonucleotides as disease-modifying agents in α-synuclein models of PD.

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Sub-regional differences and mechanisms of the short-term plasticity of dopamine overflow in striatum in mice lacking alpha-synuclein

Cited by 18 publications

References 42 publications

The dopamine patchwork of the rat nucleus accumbens core

The dopamine patchwork of the rat nucleus accumbens core

The physiological role of α‐synuclein and its relationship to Parkinson’s Disease

Selective α-Synuclein Knockdown in Monoamine Neurons by Intranasal Oligonucleotide Delivery: Potential Therapy for Parkinson’s Disease

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