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1.
Hum Mol Genet ; 26(1): 90-108, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-28007902

RESUMO

Human doublecortin (DCX) mutations are associated with severe brain malformations leading to aberrant neuron positioning (heterotopia), intellectual disability and epilepsy. The Dcx protein plays a key role in neuronal migration, and hippocampal pyramidal neurons in Dcx knockout (KO) mice are disorganized. The single CA3 pyramidal cell layer observed in wild type (WT) is present as two abnormal layers in the KO, and CA3 KO pyramidal neurons are more excitable than WT. Dcx KO mice also exhibit spontaneous epileptic activity originating in the hippocampus. It is unknown, however, how hyperexcitability arises and why two CA3 layers are observed.Transcriptome analyses were performed to search for perturbed postnatal gene expression, comparing Dcx KO CA3 pyramidal cell layers with WT. Gene expression changes common to both KO layers indicated mitochondria and Golgi apparatus anomalies, as well as increased cell stress. Intriguingly, gene expression analyses also suggested that the KO layers differ significantly from each other, particularly in terms of maturity. Layer-specific molecular markers and BrdU birthdating to mark the final positions of neurons born at distinct timepoints revealed inverted layering of the CA3 region in Dcx KO animals. Notably, many early-born 'outer boundary' neurons are located in an inner position in the Dcx KO CA3, superficial to other pyramidal neurons. This abnormal positioning likely affects cell morphology and connectivity, influencing network function. Dissecting this Dcx KO phenotype sheds light on coordinated developmental mechanisms of neuronal subpopulations, as well as gene expression patterns contributing to a bi-layered malformation associated with epilepsy.


Assuntos
Hipocampo/metabolismo , Hipocampo/patologia , Proteínas Associadas aos Microtúbulos/fisiologia , Neurônios/metabolismo , Neurônios/patologia , Neuropeptídeos/fisiologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/ultraestrutura , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/patologia , Região CA1 Hipocampal/ultraestrutura , Região CA3 Hipocampal/metabolismo , Região CA3 Hipocampal/patologia , Região CA3 Hipocampal/ultraestrutura , Proteínas do Domínio Duplacortina , Proteína Duplacortina , Feminino , Hipocampo/ultraestrutura , Processamento de Imagem Assistida por Computador , Microdissecção e Captura a Laser , Masculino , Camundongos , Camundongos Knockout , Microscopia Confocal , Neurônios/ultraestrutura
2.
Eur J Neurosci ; 49(6): 794-804, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29791756

RESUMO

Diet influences dopamine transmission in motor- and reward-related basal ganglia circuitry. In part, this reflects diet-dependent regulation of circulating and brain insulin levels. Activation of striatal insulin receptors amplifies axonal dopamine release in brain slices, and regulates food preference in vivo. The effect of insulin on dopamine release is indirect, and requires striatal cholinergic interneurons that express insulin receptors. However, insulin also acts directly on dopamine axons to increase dopamine uptake by promoting dopamine transporter (DAT) surface expression, counteracting enhanced dopamine release. Here, we determined the functional consequences of acute insulin exposure and chronic diet-induced changes in insulin on DAT activity after evoked dopamine release in striatal slices from adult ad-libitum fed (AL) rats and mice, and food-restricted (FR) or high-fat/high-sugar obesogenic (OB) diet rats. Uptake kinetics were assessed by fitting evoked dopamine transients to the Michaelis-Menten equation and extracting Cpeak and Vmax . Insulin (30 nm) increased both parameters in the caudate putamen and nucleus accumbens core of AL rats in an insulin receptor- and PI3-kinase-dependent manner. A pure effect of insulin on uptake was unmasked using mice lacking striatal acetylcholine, in which increased Vmax caused a decrease in Cpeak . Diet also influenced Vmax , which was lower in FR vs. AL. The effects of insulin on Cpeak and Vmax were amplified by FR but blunted by OB, consistent with opposite consequences of these diets on insulin levels and insulin receptor sensitivity. Overall, these data reveal acute and chronic effects of insulin and diet on dopamine release and uptake that will influence brain reward pathways.


Assuntos
Encéfalo/metabolismo , Dieta Hiperlipídica , Dopamina/metabolismo , Insulina/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Dopamina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/farmacologia , Insulina/farmacologia , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Masculino , Núcleo Accumbens/efeitos dos fármacos , Ratos Sprague-Dawley , Receptor de Insulina/efeitos dos fármacos , Receptor de Insulina/metabolismo
3.
Neurobiol Dis ; 92(Pt A): 18-45, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26299390

RESUMO

A wide spectrum of focal, regional, or diffuse structural brain abnormalities, collectively known as malformations of cortical development (MCDs), frequently manifest with intellectual disability (ID), epilepsy, and/or autistic spectrum disorder (ASD). As the acronym suggests, MCDs are perturbations of the normal architecture of the cerebral cortex and hippocampus. The pathogenesis of these disorders remains incompletely understood; however, one area that has provided important insights has been the study of neuronal migration. The amalgamation of human genetics and experimental studies in animal models has led to the recognition that common genetic causes of neurodevelopmental disorders, including many severe epilepsy syndromes, are due to mutations in genes regulating the migration of newly born post-mitotic neurons. Neuronal migration genes often, though not exclusively, code for proteins involved in the function of the cytoskeleton. Other cellular processes, such as cell division and axon/dendrite formation, which similarly depend on cytoskeletal functions, may also be affected. We focus here on how the susceptibility of the highly organized neocortex and hippocampus may be due to their laminar organization, which involves the tight regulation, both temporally and spatially, of gene expression, specialized progenitor cells, the migration of neurons over large distances and a birthdate-specific layering of neurons. Perturbations in neuronal migration result in abnormal lamination, neuronal differentiation defects, abnormal cellular morphology and circuit formation. Ultimately this results in disorganized excitatory and inhibitory activity leading to the symptoms observed in individuals with these disorders.


Assuntos
Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiopatologia , Citoesqueleto/metabolismo , Epilepsia/fisiopatologia , Malformações do Desenvolvimento Cortical do Grupo II/fisiopatologia , Movimento Celular/fisiologia , Humanos , Neurônios/fisiologia
4.
J Neurochem ; 118(5): 714-20, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21689106

RESUMO

Dopamine (DA) is an important transmitter in both motor and limbic pathways. We sought to investigate the role of D(1)-receptor activation in axonal DA release regulation in dorsal striatum using a D(1)-receptor antagonist, SKF-83566. Evoked DA release was monitored in rat striatal slices using fast-scan cyclic voltammetry. SKF-83566 caused a concentration-dependent increase in peak single-pulse evoked extracellular DA concentration, with a maximum increase of ∼ 65% in 5 µM SKF-83566. This was accompanied by a concentration-dependent increase in extracellular DA concentration clearance time. Both effects were occluded by nomifensine (1 µM), a dopamine transporter (DAT) inhibitor, suggesting that SKF-83566 acted via the DAT. We tested this by examining [(3)H]DA uptake into LLc-PK cells expressing rat DAT, and confirmed that SKF-83566 is a competitive DAT inhibitor with an IC(50) of 5.7 µM. Binding studies with [(3)H]CFT, a cocaine analog, showed even more potent action of SKF-83566 at the DAT cocaine binding site (IC(50) = 0.51 µM). Thus, data obtained using SKF-83566 as a D(1) DA-receptor antagonist may be confounded by concurrent DAT inhibition. More positively, however, SKF-83566 might be a candidate to attenuate cocaine effects in vivo because of the greater potency of this drug at the cocaine versus DA binding site of the DAT.


Assuntos
2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/análogos & derivados , Antagonistas de Dopamina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Dopamina/metabolismo , Prosencéfalo/efeitos dos fármacos , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Animais , Dopamina/farmacocinética , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Inibidores da Captação de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Eletroquímica/métodos , Técnicas In Vitro , Masculino , Nomifensina/farmacologia , Prosencéfalo/citologia , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Trítio/farmacocinética , Tropanos/farmacocinética
5.
Nat Commun ; 6: 8543, 2015 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-26503322

RESUMO

Insulin activates insulin receptors (InsRs) in the hypothalamus to signal satiety after a meal. However, the rising incidence of obesity, which results in chronically elevated insulin levels, implies that insulin may also act in brain centres that regulate motivation and reward. We report here that insulin can amplify action potential-dependent dopamine (DA) release in the nucleus accumbens (NAc) and caudate-putamen through an indirect mechanism that involves striatal cholinergic interneurons that express InsRs. Furthermore, two different chronic diet manipulations in rats, food restriction (FR) and an obesogenic (OB) diet, oppositely alter the sensitivity of striatal DA release to insulin, with enhanced responsiveness in FR, but loss of responsiveness in OB. Behavioural studies show that intact insulin levels in the NAc shell are necessary for acquisition of preference for the flavour of a paired glucose solution. Together, these data imply that striatal insulin signalling enhances DA release to influence food choices.


Assuntos
Neurônios Colinérgicos/metabolismo , Dopamina/metabolismo , Insulina/metabolismo , Interneurônios/metabolismo , Núcleo Accumbens/metabolismo , Obesidade/metabolismo , Obesidade/psicologia , Animais , Preferências Alimentares , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Receptor de Insulina/metabolismo , Recompensa , Transdução de Sinais
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