Nitric oxide is a diffusible messenger that plays a multitude of roles within the nervous system including modulation of cell viability. However, its role in regulating neuronal survival during a defined period of neurodevelopment has never been investigated. We discovered that expression of the messenger RNA for both neuronal and endothelial nitric oxide synthase increased in the early postnatal period in the cerebellum in vivo, whilst the expression of inducible nitric oxide synthase remained constant throughout this time in development. Whilst scavenging of nitric oxide was deleterious to the survival of early postnatal cerebellar granule neurons in vitro, this effect was lost in cultures derived at increasing postnatal ages. Conversely, sensitivity to exogenous nitric oxide increased with advancing postnatal age. Thus, we have shown that as postnatal development proceeds, cerebellar granule cells alter their in vitro survival responses to both nitric oxide inhibition and donation, revealing that the nitric oxide's effects on developing neurons vary with the stage of development studied. These findings have important consequences for our understanding of the role of nitric oxide during neuronal development.
[Show abstract][Hide abstract] ABSTRACT: As recent evidence has revealed a pro-survival role for the anti-obesity hormone leptin in the nervous system, we investigated the generality of this finding on cerebellar Purkinje and granule neurons in vitro. We found that whilst leptin promoted cerebellar Purkinje neuron survival, it had no affect on cerebellar granule cells. In addition, we discovered that leptin promoted both the outgrowth of neurites from cerebellar Purkinje neurons and increased the complexity of the neurite arbor. Thus, leptin has different effects on two neighbouring populations of neurons within the cerebellum implying specificity of its actions in the central nervous system.
[Show abstract][Hide abstract] ABSTRACT: The role of endogenous neuronal nitric oxide synthase (nNOS) gene in the development of cerebellar granule neurons (CGNs) is conflicting. Here, we tested the effect of antisense oligos (AS-ODN) on the endogenous nNOS gene and the development of the CGNs in vitro. The expression of nNOS increased in a development-dependent pattern both in terms of mRNA and protein. AS-ODN down-regulated nNOS gene, but in a posttranscriptional manner. Knockdown of nNOS protein decreased the viability of the CGNs from 7 to 13 days in culture (DIC). This activity of AS-ODN was mimicked by nNOS inhibitor I. The antagonist (nNOSi, MK-801, or ODQ) -induced decrease of cell viability was normalized by the provision of the sodium nitroprusside, an NO donor. This study provides direct evidence that endogenous nNOS, mainly by means of its principal product NO, plays an active role in sustaining the survival of developing CGNs at transition from differentiation to maturation.
[Show abstract][Hide abstract] ABSTRACT: Tumour necrosis factor-alpha (TNF-alpha) has been widely implicated in both neurodevelopment and neurodegeneration, yet its effects on individual populations of cerebellar neurons as they develop have not been fully elucidated. Therefore, we established primary neuronal cultures of developing murine cerebellar Purkinje neurons and postnatal cerebellar granule cells to determine the consequences of TNF-alpha exposure for their survival. We discovered that TNF-alpha did not affect the viability of cerebellar granule neurons at any of the ages studied, even though TNF-alpha and its receptors, TNFR1 and TNFR2, are widely expressed in the postnatal cerebellum. In addition, TNF-alpha was neither able to ameliorate, nor enhance, cell death in cerebellar granule cells elicited by a variety of stimuli including homocysteine and alcohol exposure. In contrast, in cultures established at embryonic day 16, TNF-alpha enhanced the number of cerebellar Purkinje neurons in vitro but this effect was not observed in embryonic day 19 cultures. Thus, TNF-alpha has differential and highly specific effects on different populations of cerebellar neurons as they develop.
SeongHun Yoon, Mario Zuccarello, Robert M. Rapoport
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