RESUMO
Regulation of neuritic growth is crucial for neural development, adaptation and repair. The intrinsic growth potential of nerve cells is determined by the activity of specific molecular sets, which sense environmental signals and sustain structural extension of neurites. The expression and function of these molecules are dynamically regulated by multiple mechanisms, which adjust the actual growth properties of each neuron population at different ontogenetic stages or in specific conditions. The neuronal potential for axon elongation and regeneration are restricted at the end of development by the concurrent action of several factors associated with the final maturation of neurons and of the surrounding tissue. In the adult, neuronal growth properties can be significantly modulated by injury, but they are also continuously tuned in everyday life to sustain physiological plasticity. Strict regulation of structural remodelling and neuritic elongation is thought to be required to maintain specific patterns of connectivity in the highly complex mammalian CNS. Accordingly, procedures that neutralize such mechanisms effectively boost axon growth in both intact and injured nervous system. Even in these conditions, however, aberrant connections are only formed in the presence of unusual external stimuli or experience. Therefore, growth regulatory mechanisms play an essentially permissive role by setting the responsiveness of neural circuits to environmental stimuli. The latter exert an instructive action and determine the actual shape of newly formed connections. In the light of this notion, efficient therapeutic interventions in the injured CNS should combine targeted manipulations of growth control mechanisms with task-specific training and rehabilitation paradigms.
Assuntos
Regeneração Nervosa/fisiologia , Neurônios/citologia , Animais , Animais Geneticamente Modificados , Axônios/fisiologia , Sistema Nervoso Central/citologia , Sistema Nervoso Central/crescimento & desenvolvimento , Sistema Nervoso Central/lesões , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Modelos Neurológicos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Neuritos/fisiologia , Plasticidade Neuronal , Traumatismos dos Nervos Periféricos , Nervos Periféricos/citologia , Nervos Periféricos/crescimento & desenvolvimento , Ratos , Transdução de SinaisRESUMO
Chondroitin sulfate proteoglycans are major constituents of the extracellular matrix and form perineuronal nets. Information regarding the growth-inhibitory activity of these molecules after injury is rapidly expanding. However, less is known about their physiological role in the adult undamaged CNS. Here, we investigated the function of chondroitin sulfate proteoglycans in maintaining the proper structure of Purkinje axons in the cerebellum of adult rats. To this end, we examined the morphology and distribution of intracortical Purkinje neurites after intraparenchymal injection of chondroitinase ABC. Staining with the lectin Wisteria floribunda agglutinin or 2B6 antibodies showed that this treatment efficiently removed chondroitin sulfate proteoglycans from wide areas of the cerebellar cortex. In the same sites, there was a profuse outgrowth of terminal branches from the Purkinje infraganglionic plexus, which invaded the deeper regions of the granular layer. In contrast, myelinated axon segments were not affected and maintained their normal relationship with oligodendroglial sheaths. Purkinje axon sprouting was first evident at 4 d and increased further at 7 d after enzyme application. Within 42 d, the expression pattern of chondroitin sulfate proteoglycans gradually recovered, whereas axonal modifications progressively regressed. Our results show that, in the absence of injury or novel external stimuli, degradation of chondroitin sulfate proteoglycans is sufficient to induce Purkinje axon sprouting but not the formation of long-lasting synaptic contacts. Together with other growth-inhibitory molecules, such as myelin-associated proteins, chondroitin sulfate proteoglycans restrict structural plasticity of intact Purkinje axons to maintain normal wiring patterns in the adult cerebellar cortex.
Assuntos
Axônios/fisiologia , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Regeneração Nervosa/fisiologia , Células de Purkinje/fisiologia , Animais , Axônios/ultraestrutura , Cerebelo/citologia , Cerebelo/metabolismo , Condroitina ABC Liase/farmacologia , Proteoglicanas de Sulfatos de Condroitina/efeitos dos fármacos , Bainha de Mielina/fisiologia , Células de Purkinje/ultraestrutura , Ratos , Ratos Wistar , Distribuição TecidualRESUMO
A key component of the astrocyte cytoskeleton is the glial fibrillary acidic protein (GFAP), which plays an essential role in neuron/astrocyte interactions. Environmental conditioning, such as visual experience manipulation, can affect neuronal and/or glial plasticity in specific brain areas. Previous work from our laboratory showed that short light deprivation throughout the period of GFAP maturation does not influence the expression profile of GFAP in mouse visual cortex; however, it was strong enough to affect neuronal phenotype. It was suggested that visual experience controls the maturation of the neuronal circuitry in this brain area. Therefore, to see whether the modifications of neuronal activity induced by light deprivation affect the maintenance of normal astrocytic phenotype, the dark rearing protocol was extended until the adult life. GFAP-immunoreactive cells were dramatically affected, showing an 80% decrease in number. In addition, GFAP protein level exhibited a 50% reduction, while its mRNA remained unaffected. Besides the visual cortex, two other areas of the brain not directly involved in vision, the hippocampus and the motor cortex, were chosen as internal controls. Unexpectedly, also in these areas, astrocytes were affected by light deprivation. The present results show that lack of visual experience for long periods of time deeply affects glial phenotype not only in visual areas but also in brain regions not directly involved in sensory processing.
Assuntos
Proteína Glial Fibrilar Ácida/fisiologia , Privação Sensorial/fisiologia , Córtex Visual/fisiologia , Animais , Contagem de Células , Escuridão , Proteína Glial Fibrilar Ácida/genética , Hipocampo/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Córtex Visual/citologia , Córtex Visual/crescimento & desenvolvimentoRESUMO
We analysed the specific effects of IL-1beta immunoneutralization on the expression of IL-6 in different pure cultures of neurones and glia after both experimental subliminal hypoxia and recovery. Whereas the IL-1beta-deprivation signal induced a decrease in IL-6 expression and release of normoxic neurones, it provoked an increase in IL-6 protein in hypoxic neurones. Moreover, the direct correlation between IL-1beta and IL-6, observed in normal and recovering neuronal cultures, was reversed in hypoxic conditions. These reversals were not observed in glial cells, in which IL-1beta immunosuppression led to a decrease in IL-6 under all conditions considered. In conclusion, the IL-1beta modulates IL-6 in different ways according to the ambient physiological or pathological conditions, and also acts via different mechanisms, depending on the cellular phenotype.
Assuntos
Interleucina-1/fisiologia , Interleucina-6/genética , Neuroglia/metabolismo , Neurônios/metabolismo , Animais , Ensaio de Imunoadsorção Enzimática , Feminino , Imuno-Histoquímica , Gravidez , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
In the last few years Purkinje cells have become a most interesting model to investigate cellular/molecular mechanisms of axon regeneration and plasticity. Adult Purkinje cells are most peculiar for their weak cell body response to axotomy, which is accompanied by a strong resistance to injury and a virtually absolute inability to regenerate severed neurites, even in the presence of favourable environmental conditions. The same neurons show a vigorous intrinsic inclination toward axonal sprouting and structural plasticity, which can be elicited by removing extrinsic growth-inhibitory cues. These features gradually develop during early postnatal life, but the underlying mechanisms and biological significance remain unclear. This article reviews recent studies aimed at addressing these questions with respect to the general issue of brain repair. Indeed, understanding the reasons for the extremely poor regenerative capacity of Purkinje cells will be most important to elucidate basic biological mechanisms of axon regeneration and plasticity, and to promote circuit rewiring in the adult CNS.
Assuntos
Axônios/fisiologia , Córtex Cerebelar/crescimento & desenvolvimento , Regeneração Nervosa/fisiologia , Plasticidade Neuronal/fisiologia , Células de Purkinje/fisiologia , Envelhecimento/fisiologia , Animais , Axônios/ultraestrutura , Córtex Cerebelar/citologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Cones de Crescimento/metabolismo , Cones de Crescimento/ultraestrutura , Inibidores do Crescimento/metabolismo , Humanos , Fatores de Crescimento Neural/metabolismo , Células de Purkinje/citologiaRESUMO
Mammalian visual cortex is immature at birth and develops gradually during defined postnatal temporal windows. In the present work, we studied the maturation of astrocytes in developing mouse visual cortex (VC). The cellular distribution and the level of glial fibrillary acidic protein (GFAP) were analyzed by immunohistochemistry and Western blotting. Experiments were performed at different postnatal ages: postnatal day 12 (P12), before eye opening; P24, corresponding roughly to the peak of the critical period for monocular deprivation, and P60, after the end of the critical period. At P12, GFAP immunoreactivity (IR) was distributed throughout all cortical layers. At P24, there was a prominent localization of GFAP IR in layers I, II, and VI, while cortical layers III, IV, and V contained no longer GFAP IR cells. No differences were found in GFAP IR between P24 and P60. Western blot analysis revealed a reduction of GFAP expression in the VC at P24 with respect to P12 and no significant difference between P60 and P24. These results show that GFAP expression is modulated during early postnatal development. To know whether visual experience influences the maturation pattern of GFAP expression, mice were dark-reared from P12 to P24. Dark rearing did not change the distribution and the expression of GFAP. Our results indicate that maturation of GFAP expression occurs early in postnatal development in mouse VC. In addition, we showed that GFAP development is not affected by visual deprivation.