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1.
Sci Rep ; 11(1): 1149, 2021 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441874

RESUMO

Bladder and bowel dysfunction (BBD) is a common yet underdiagnosed paediatric entity that describes lower urinary tract symptoms (LUTS) accompanied by abnormal bowel patterns manifested as constipation and/or encopresis. LUTS usually manifest as urgency, urinary frequency, incontinence, and urinary tract infections (UTI). Despite increasing recognition of BBD as a risk factor for long-term urinary tract problems including recurrent UTI, vesicoureteral reflux, and renal scarring, the mechanisms underlying BBD have been unclear, and treatment remains empirical. We investigated how constipation affects the lower urinary tract function using a juvenile murine model of functional constipation. Following four days of functional constipation, animals developed LUTS including urinary frequency and detrusor overactivity evaluated by awake cystometry. Physiological examination of detrusor function in vitro using isolated bladder strips, demonstrated a significant increase in spontaneous contractions without affecting contractile force in response to electrical field stimulation, carbachol, and KCl. A significant upregulation of serotonin receptors, Htr2a and Htr2c, was observed in the bladders from mice with constipation, paralleled with augmented spontaneous contractions after pre-incubation of the bladder strips with 0.5 µM of serotonin. These results suggest that constipation induced detrusor overactivity and increased excitatory serotonin receptor activation in the urinary bladder, which contributes to the development of BBD.


Assuntos
Canais de Cálcio/metabolismo , Constipação Intestinal/complicações , Receptor 5-HT2A de Serotonina/metabolismo , Transdução de Sinais , Canais de Cátion TRPV/metabolismo , Bexiga Urinária Hiperativa/etiologia , Bexiga Urinária/fisiopatologia , Animais , Constipação Intestinal/metabolismo , Constipação Intestinal/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Bexiga Urinária/metabolismo , Bexiga Urinária Hiperativa/metabolismo , Bexiga Urinária Hiperativa/fisiopatologia
2.
FEBS J ; 283(24): 4569-4582, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27797453

RESUMO

Apoptotic cell death is critical for the early development of the nervous system, but once the nervous system is established, the apoptotic pathway becomes highly restricted in mature neurons. However, the mechanisms underlying this increased resistance to apoptosis in these mature neurons are not completely understood. We have previously found that members of the miR-29 family of microRNAs (miRNAs) are induced with neuronal maturation and that overexpression of miR-29 was sufficient to restrict apoptosis in neurons. To determine whether endogenous miR-29 alone was responsible for the inhibition of cytochrome c release in mature neurons, we examined the status of the apoptotic pathway in sympathetic neurons deficient for all three miR-29 family members. Unexpectedly, we found that the apoptotic pathway remained largely restricted in miR-29-deficient mature neurons. We therefore probed for additional mechanisms by which mature neurons resist apoptosis. We identify miR-24 as another miRNA that is upregulated in the maturing cerebellum and sympathetic neurons that can act redundantly with miR-29 by targeting a similar repertoire of prodeath BH3-only genes. Overall, our results reveal that mature neurons engage multiple redundant brakes to restrict the apoptotic pathway and ensure their long-term survival.


Assuntos
Apoptose/genética , Citocromos c/metabolismo , MicroRNAs/genética , Neurônios/metabolismo , Regiões 3' não Traduzidas/genética , Animais , Animais Recém-Nascidos , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteína 11 Semelhante a Bcl-2/genética , Proteína 11 Semelhante a Bcl-2/metabolismo , Células Cultivadas , Gânglios/citologia , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Camundongos , Microscopia de Fluorescência , Microscopia de Vídeo , Mitocôndrias/metabolismo , Neurônios/citologia , Proteínas Proto-Oncogênicas , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
3.
Front Cell Neurosci ; 9: 144, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25941472

RESUMO

Astrocytes are the predominant glial type in the central nervous system and play important roles in assisting neuronal function and network activity. Astrocytes exhibit complex signaling systems that are essential for their normal function and the homeostasis of the neural network. Altered signaling in astrocytes is closely associated with neurological and psychiatric diseases, suggesting tremendous therapeutic potential of these cells. To further understand astrocyte function in health and disease, it is important to study astrocytic signaling in vivo. In this review, we discuss molecular tools that enable the selective manipulation of astrocytic signaling, including the tools to selectively activate and inactivate astrocyte signaling in vivo. Lastly, we highlight a few tools in development that present strong potential for advancing our understanding of the role of astrocytes in physiology, behavior, and pathology.

4.
J Vis Exp ; (85)2014 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-24686723

RESUMO

Close to two decades of research has established that astrocytes in situ and in vivo express numerous G protein-coupled receptors (GPCRs) that can be stimulated by neuronally-released transmitter. However, the ability of astrocytic receptors to exhibit plasticity in response to changes in neuronal activity has received little attention. Here we describe a model system that can be used to globally scale up or down astrocytic group I metabotropic glutamate receptors (mGluRs) in acute brain slices. Included are methods on how to prepare parasagittal hippocampal slices, construct chambers suitable for long-term slice incubation, bidirectionally manipulate neuronal action potential frequency, load astrocytes and astrocyte processes with fluorescent Ca(2+) indicator, and measure changes in astrocytic Gq GPCR activity by recording spontaneous and evoked astrocyte Ca(2+) events using confocal microscopy. In essence, a "calcium roadmap" is provided for how to measure plasticity of astrocytic Gq GPCRs. Applications of the technique for study of astrocytes are discussed. Having an understanding of how astrocytic receptor signaling is affected by changes in neuronal activity has important implications for both normal synaptic function as well as processes underlying neurological disorders and neurodegenerative disease.


Assuntos
Astrócitos/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Potenciais de Ação/fisiologia , Animais , Astrócitos/metabolismo , Hipocampo/citologia , Hipocampo/metabolismo , Hipocampo/fisiologia , Camundongos , Neurônios/metabolismo , Técnicas de Patch-Clamp/métodos , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo
5.
PLoS One ; 7(11): e49637, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23166735

RESUMO

Very little is known about the ability of astrocytic receptors to exhibit plasticity as a result of changes in neuronal activity. Here we provide evidence for bidirectional scaling of astrocytic group I metabotropic glutamate receptor signaling in acute mouse hippocampal slices following long-term changes in neuronal firing rates. Plasticity of astrocytic mGluRs was measured by recording spontaneous and evoked Ca²âº elevations in both astrocytic somata and processes. An exogenous astrocytic Gq G protein-coupled receptor was resistant to scaling, suggesting that the alterations in astrocyte Ca²âº signaling result from changes in activity of the surface mGluRs rather than a change in intracellular G protein signaling molecules. These findings suggest that astrocytes actively detect shifts in neuronal firing rates and adjust their receptor signaling accordingly. This type of long-term plasticity in astrocytes resembles neuronal homeostatic plasticity and might be important to ensure an optimal or expected level of input from neurons.


Assuntos
Potenciais de Ação , Astrócitos/metabolismo , Neurônios/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Transdução de Sinais , Animais , Cálcio/metabolismo , Sinalização do Cálcio , Comunicação Celular , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Hipocampo/metabolismo , Microdomínios da Membrana/metabolismo , Camundongos , Técnicas de Patch-Clamp , Potássio/metabolismo , Receptores Acoplados a Proteínas G/metabolismo
6.
Drug Discov Today Dis Models ; 5(1): 19-25, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-19444332

RESUMO

The mammalian central nervous system (CNS) is populated very early in development by tissue macrophages referred to as microglia. By adulthood, this CNS-resident population is found in all regions of the brain and spinal cord. Despite nearly a century of study, the in vivo function of microglia and the extent that they contribute to the onset, progression and recovery from neuroinflammatory disorders is still a subject of debate. Partly, the debate of whether activated microglia promote neuroprotection or neurodegeneration is fueled by the contrasting results derived from the different models used to assay microglial function. Here we discuss the strengths, weaknesses and utility of some of the most commonly used in vivo and in vitro models.

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