Purkiss, Richard John; (1994) Neurotrophins, immediate early genes and neuronal cell death. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The selective nature of the neuronal cell death that accompanies excitotoxic lesions of the striatum has been predominantly attributed to possible receptor heterogeneities amongst the various classes of striatal neurons. The involvement of any endogenous protective mechanism in contributing to this selectivity remain largely unexplored. Intrastriatal infusions of quinolinic acid were found to result in a relative sparing of the striatal cholinergic neuron, that could be enhanced by lowering glucocorticoid levels using metyrapone or reduced by raising glucocorticoid concentrations with dexamethasone. This relative sparing of the cholinergic neuron was accompanied by a characteristic pattern of expression of immediate early genes of the AP-1 family: c-fos mRNA and protein, and jun B mRNA were induced rapidly and transiently within the periphery of the striatum and throughout the ipsilateral cortex, whilst c-jun mRNA and protein, jun D mRNA and fos B mRNA all showed a latent and prolonged pattern of expression in the central lesioned area of the striatum. Furthermore, NGF mRNA and protein, and NT-3 mRNA were all found to be upregulated in the ipsilateral striatum by 24 hours post-lesion; both NGF mRNA and NI'-3 mRNA reached a maximum expression by 48 hours, and persisted until 7 days. At the earliest time points (9 hours), enhanced expression of NGF mRNA and NT-3 mRNA was restricted to areas immediately proximal to the lesion tract; this subsequently expanded to encompass the majority of the striatum by 24 hours, exhibiting a spatial expression very similar to that of c-jun mRNA, jun D mRNA and fos B mRNA at the same time point, as well as to the area of neurodegeneration revealed by histochemical techniques. In the same animals, BDNF mRNA showed an early and transient (2-9 hours) upregulation in discrete regions of the ipsilateral cortex but remained at constitutive levels in the ipsilateral striatum. A prior injection of metyrapone was found to bring forward the expression of both NGF mRNA and NT-3 mRNA, whilst a co-infusion with dexamethasone had the effect of delaying their expression. These results highlight a potential mechanism for the relative sparing of the striatal cholinergic neuron following excitotoxic neuronal injury via the endogenous upregulation of NGF and NT-3 by compromised neurons as well as perhaps glia. They also indicate a potential role tor c-jun, fos B and jun D in the transcriptional upregulation of both NGF and NT-3

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