RESUMO
Adult neuronal precursors retain the remarkable capacity to migrate long distances from the posterior (subventricular zone) to the most anterior [olfactory bulb (OB)] parts of the brain. The knowledge about the mechanisms that keep neuronal precursors in the migratory stream and organize this long-distance migration is incomplete. Here we show that blood vessels precisely outline the migratory stream for new neurons in the adult mammalian forebrain. Real-time video imaging of cell migration in the acute slices demonstrate that neuronal precursors are retained in the migratory stream and guided into the OB by blood vessels that serve as a physical substrate for migrating neuroblasts. Our data suggest that endothelial cells of blood vessels synthesize brain-derived neurotrophic factor (BDNF) that fosters neuronal migration via p75NTR expressed on neuroblasts. Interestingly, GABA released from neuroblasts induces Ca(2+)-dependent insertion of high-affinity TrkB receptors on the plasma membrane of astrocytes that trap extracellular BDNF. We hypothesize that this renders BDNF unavailable for p75NTR-expressing migrating cells and leads to their entrance into the stationary period. Our findings provide new insights into the functional organization of substrates that facilitate the long-distance journey of adult neuronal precursors.
Assuntos
Células-Tronco Adultas/fisiologia , Vasos Sanguíneos/fisiologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Movimento Celular/fisiologia , Neurônios/fisiologia , Prosencéfalo/fisiologia , Transdução de Sinais/fisiologia , Animais , Astrócitos , Bicuculina/farmacologia , Compostos de Boro/farmacologia , Fator Neurotrófico Derivado do Encéfalo/genética , Bromodesoxiuridina/metabolismo , Cálcio/metabolismo , Movimento Celular/genética , Células Cultivadas , Células Endoteliais/fisiologia , Transportador 1 de Aminoácido Excitatório/genética , Citometria de Fluxo/métodos , Antagonistas GABAérgicos/farmacologia , Expressão Gênica/fisiologia , Proteína Glial Fibrilar Ácida/metabolismo , Glutamato Descarboxilase/deficiência , Proteínas de Fluorescência Verde/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia de Vídeo/métodos , Neurônios/efeitos dos fármacos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Prosencéfalo/citologia , Transporte Proteico/efeitos dos fármacos , RNA Interferente Pequeno/farmacologia , Receptor trkB/metabolismo , Receptores de Fator de Crescimento Neural/deficiência , Transdução de Sinais/genética , Técnicas de Cultura de Tecidos , Ácido gama-Aminobutírico/farmacologiaRESUMO
Huntington's disease (HD) is characterized by the atrophy of the striatum due to losses of projection neurons, while interneurons are relatively spared. However, little is known about the fate of the large interneurons that express calretinin (Cr) in HD. We addressed this issue by applying a double immunofluorescent labeling technique to postmortem striatum from HD patients and controls. We compared the distribution and density of Cr-positive (+) interneurons and their degree of choline acetyltransferase (ChAT) coexpression in normal and HD cases. Large interneurons containing only Cr, ChAT, or both occurred in the normal human striatum and a twofold decrease in the density of Cr+/ChAT+ and Cr-/ChAT+ neurons was recorded in HD striatum compared to controls. However, studies undertaken with neurokinin-1 receptor as a marker of large Cr+ and ChAT+ neurons revealed that these neurons are selectively spared in HD. Hence, the apparent decrease in the number of Cr+/ChAT+ and Cr-/ChAT+ neurons in HD is better explained by a diminution in the expression of Cr and ChAT than by the degeneration of these cells. Altogether, our data suggest that neurodegenerative processes at play in HD affect the expression of Cr and ChAT in the large striatal interneurons without causing their death.
Assuntos
Corpo Estriado/patologia , Doença de Huntington/patologia , Interneurônios/metabolismo , Proteína G de Ligação ao Cálcio S100/metabolismo , Adulto , Calbindina 2 , Contagem de Células/métodos , Colina O-Acetiltransferase/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptores da Neurocinina-1/metabolismoRESUMO
Neurogenesis in the adult brain occurs predominantly in the two regions, the subventricular zone (SVZ) bordering the lateral ventricle and subgranular zone (SGZ) of the hippocampus. The neuronal precursors are produced in the specialized microenvironment called neurovasculature niche. Recent evidences indicate that in addition to neurogenesis promoting environment, vasculature also serves as a substrate for migration for these newly generated cells. Importantly, under some pathological condition, including stroke, neurogenesis is enhanced in the adult brain. Newly generated neuronal precursors migrate to the sites of injury along the blood vessels and try to integrate to the damaged brain circuitry. This self-healing capacity of the adult brain is, however, insufficient to produce a noticeable amelioration in the affected neuronal network since only a tiny proportion of cells succeed to integrate and survive. Here we review the mechanisms of neuronal recruitment into the post-stroke regions with particular attention to the guidance of neuronal precursors along the blood vessels. We also outline some of the molecular factors that have been used or have a potential to be employed to improve the cell recruitment into the sites of injury.