Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
PNAS Nexus ; 2(3): pgad044, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36909827

RESUMO

Dopamine neurotransmission in the striatum is central to many normal and disease functions. Ventral midbrain dopamine neurons exhibit ongoing tonic firing that produces low extrasynaptic levels of dopamine below the detection of conventional extrasynaptic cyclic voltammetry (∼10-20 nanomolar), with superimposed bursts that can saturate the dopamine uptake transporter and produce transient micromolar concentrations. The bursts are known to lead to marked presynaptic plasticity via multiple mechanisms, but analysis methods for these kinetic parameters are limited. To provide a deeper understanding of the mechanics of the modulation of dopamine neurotransmission by physiological, genetic, and pharmacological means, we present three computational models of dopamine release with different levels of spatiotemporal complexity to analyze in vivo fast-scan cyclic voltammetry recordings from the dorsal striatum of mice. The models accurately fit to cyclic voltammetry data and provide estimates of presynaptic dopamine facilitation/depression kinetics and dopamine transporter reuptake kinetics, and we used the models to analyze the role of synuclein proteins in neurotransmission. The models' results support recent findings linking the presynaptic protein α-synuclein to the short-term facilitation and long-term depression of dopamine release, as well as reveal a new role for ß-synuclein and/or γ-synuclein in the long-term regulation of dopamine reuptake.

2.
Cell Rep ; 42(3): 112231, 2023 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-36920906

RESUMO

Auxilin participates in the uncoating of clathrin-coated vesicles (CCVs), thereby facilitating synaptic vesicle (SV) regeneration at presynaptic sites. Auxilin (DNAJC6/PARK19) loss-of-function mutations cause early-onset Parkinson's disease (PD). Here, we utilized auxilin knockout (KO) mice to elucidate the mechanisms through which auxilin deficiency and clathrin-uncoating deficits lead to PD. Auxilin KO mice display cardinal features of PD, including progressive motor deficits, α-synuclein pathology, nigral dopaminergic loss, and neuroinflammation. Significantly, treatment with L-DOPA ameliorated motor deficits. Unbiased proteomic and neurochemical analyses of auxilin KO brains indicated dopamine dyshomeostasis. We validated these findings by demonstrating slower dopamine reuptake kinetics in vivo, an effect associated with dopamine transporter misrouting into axonal membrane deformities in the dorsal striatum. Defective SV protein sorting and elevated synaptic autophagy also contribute to ineffective dopamine sequestration and compartmentalization, ultimately leading to neurodegeneration. This study provides insights into how presynaptic endocytosis deficits lead to dopaminergic vulnerability and pathogenesis of PD.


Assuntos
Doença de Parkinson , Camundongos , Animais , Doença de Parkinson/patologia , Vesículas Sinápticas/metabolismo , Auxilinas/genética , Auxilinas/metabolismo , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Proteômica , Transporte Proteico , Substância Negra/metabolismo
3.
Genes (Basel) ; 12(8)2021 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-34440340

RESUMO

α-Synuclein (α-Syn) is a small cytosolic protein associated with a range of cellular compartments, including synaptic vesicles, the nucleus, mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosomes. In addition to its physiological role in regulating presynaptic function, the protein plays a central role in both sporadic and familial Parkinson's disease (PD) via a gain-of-function mechanism. Because of this, several recent strategies propose to decrease α-Syn levels in PD patients. While these therapies may offer breakthroughs in PD management, the normal functions of α-Syn and potential side effects of its depletion require careful evaluation. Here, we review recent evidence on physiological and pathological roles of α-Syn in regulating activity-dependent signal transduction and gene expression pathways that play fundamental role in synaptic plasticity.


Assuntos
Expressão Gênica/fisiologia , alfa-Sinucleína/genética , Humanos , Plasticidade Neuronal/fisiologia , Doença de Parkinson/genética , Doença de Parkinson/patologia , Transdução de Sinais/fisiologia
4.
Proc Natl Acad Sci U S A ; 117(51): 32701-32710, 2020 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-33273122

RESUMO

α-Synuclein is expressed at high levels at presynaptic terminals, but defining its role in the regulation of neurotransmission under physiologically relevant conditions has proven elusive. We report that, in vivo, α-synuclein is responsible for the facilitation of dopamine release triggered by action potential bursts separated by short intervals (seconds) and a depression of release with longer intervals between bursts (minutes). These forms of presynaptic plasticity appear to be independent of the presence of ß- and γ-synucleins or effects on presynaptic calcium and are consistent with a role for synucleins in the enhancement of synaptic vesicle fusion and turnover. These results indicate that the presynaptic effects of α-synuclein depend on specific patterns of neuronal activity.


Assuntos
Dopamina/metabolismo , Neurônios/metabolismo , Substância Negra/metabolismo , alfa-Sinucleína/metabolismo , Anestésicos Inalatórios/farmacologia , Animais , Sinalização do Cálcio , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Feminino , Isoflurano/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurotransmissores/metabolismo , Substância Negra/citologia , Vesículas Sinápticas/metabolismo , alfa-Sinucleína/genética , gama-Sinucleína/metabolismo
5.
Elife ; 82019 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-31580257

RESUMO

Functional diversity of midbrain dopamine (DA) neurons ranges across multiple scales, from differences in intrinsic properties and connectivity to selective task engagement in behaving animals. Distinct in vitro biophysical features of DA neurons have been associated with different axonal projection targets. However, it is unknown how this translates to different firing patterns of projection-defined DA subpopulations in the intact brain. We combined retrograde tracing with single-unit recording and labelling in mouse brain to create an in vivo functional topography of the midbrain DA system. We identified differences in burst firing among DA neurons projecting to dorsolateral striatum. Bursting also differentiated DA neurons in the medial substantia nigra (SN) projecting either to dorsal or ventral striatum. We found differences in mean firing rates and pause durations among ventral tegmental area (VTA) DA neurons projecting to lateral or medial shell of nucleus accumbens. Our data establishes a high-resolution functional in vivo landscape of midbrain DA neurons.


Assuntos
Axônios/fisiologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/fisiologia , Mesencéfalo/fisiologia , Potenciais de Ação/fisiologia , Animais , Corpo Estriado/fisiologia , Camundongos , Núcleo Accumbens/fisiologia , Substância Negra/fisiologia , Área Tegmentar Ventral/fisiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...