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1.
J Exp Med ; 214(8): 2271-2282, 2017 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-28698285

RESUMO

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a neurological syndrome characterized by small vessel disease (SVD), stroke, and vascular cognitive impairment and dementia caused by mutations in NOTCH3 No therapies are available for this condition. Loss of mural cells, which encompass pericytes and vascular smooth muscle cells, is a hallmark of CADASIL and other SVDs, including diabetic retinopathy, resulting in vascular instability. Here, we showed that Notch3 signaling is both necessary and sufficient to support mural cell coverage in arteries using genetic rescue in Notch3 knockout mice. Furthermore, we show that systemic administration of an agonist Notch3 antibody prevents mural cell loss and modifies plasma proteins associated with Notch3 activity, including endostatin/collagen 18α1 and Notch3 extracellular domain in mice with the C455R mutation, a CADASIL variant associated with Notch3 loss of function. These findings open opportunities for the treatment of CADASIL and other SVDs by modulating Notch3 signaling.


Assuntos
Anticorpos/uso terapêutico , CADASIL/terapia , Receptor Notch3/fisiologia , Animais , Anticorpos/imunologia , Modelos Animais de Doenças , Feminino , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Músculo Liso Vascular/citologia , Músculo Liso Vascular/fisiopatologia , Pericitos/fisiologia , Receptor Notch3/imunologia , Transdução de Sinais/fisiologia
2.
J Neurochem ; 122(5): 900-10, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22168837

RESUMO

GABAergic transmission in the neostriatum plays a central role in motor coordination, in which a plethora of GABA-A receptor subunits combine to modulate neural inhibition. GABAρ receptors were originally described in the mammalian retina. These receptors possess special electrophysiological and pharmacological properties, forming a characteristic class of ionotropic receptors. In previous studies, we suggested that GABAρ receptors are expressed in the neostriatum, and in this report we show that they are indeed present in all the calretinin-positive interneurons of the neostriatum. In addition, they are located in calbindin-positive interneurons and projection neurons that express the dopamine D(2) receptor. GABAρ receptors were also located in 30% of the glial fibrillary acidic protein-positive cells, and may therefore also contribute to gliotransmission. Quantitative reverse transcription-PCR suggested that the mRNAs of this receptor do not express as much as in the retina, and that GABAρ2 is more abundant than GABAρ1. Electrophysiological recordings in brain slices provided evidence of neurons expressing a cis-4-aminocrotonic acid-activated, 1,2,5,6-tetrahydropyridine-4-yl methylphosphinic acid-sensitive ionotropic GABA receptor, indicating the presence of functional GABAρ receptors in the neostriatum. Finally, electron-microscopy and immunogold located the receptors mainly in perisynaptic as well as in extrasynaptic sites. All these observations reinforce the importance of GABAρ receptors in the neostriatum and contribute to the diversity of inhibitory regulation in this area.


Assuntos
Proteína Glial Fibrilar Ácida/metabolismo , Neostriado/citologia , Neuroglia/metabolismo , Neurônios/fisiologia , Receptores de GABA-A/metabolismo , Animais , Calbindinas , Interações Medicamentosas , GABAérgicos/farmacologia , Regulação da Expressão Gênica/genética , Proteínas de Fluorescência Verde/genética , Técnicas In Vitro , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/genética , Camundongos , Camundongos Transgênicos , Microscopia Imunoeletrônica , Neuroglia/ultraestrutura , Neurônios/classificação , Neurônios/efeitos dos fármacos , Neurônios/ultraestrutura , Técnicas de Patch-Clamp , RNA Mensageiro/metabolismo , Receptores de Dopamina D1/genética , Receptores de Dopamina D2/genética , Receptores de GABA-A/genética , Proteína G de Ligação ao Cálcio S100/metabolismo , Ácido gama-Aminobutírico/farmacologia
3.
Neurosci Lett ; 500(1): 20-5, 2011 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-21683123

RESUMO

A bicuculline-resistant and TPMPA-sensitive GABAergic component was identified in hippocampal neurons in culture and in acute isolated brain slices. In both preparations, total GABAergic activity showed two inactivation kinetics: fast and slow. RT-PCR, in situ hybridization (ISH) and immunohistochemistry detected expression of GABAρ subunits. Immunogold and electron microscopy indicated that the receptors are mostly extrasynaptic. In addition, by RT-PCR and immunofluorescence we found GABAρ present in amygdala and visual cortex.


Assuntos
Tonsila do Cerebelo/fisiologia , Hipocampo/fisiologia , Neurônios/fisiologia , Receptores de GABA-A/fisiologia , Córtex Visual/fisiologia , Animais , Embrião não Mamífero/citologia , Hipocampo/citologia , Imuno-Histoquímica , Hibridização In Situ , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos C57BL , Potenciais Pós-Sinápticos em Miniatura , Técnicas de Patch-Clamp , Subunidades Proteicas/fisiologia , Células Piramidais/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sinapses/fisiologia
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