A role for transforming growth factor alpha as an inducer of astrogliosis.

TGFalpha is a member of the epidermal growth factor (EGF) family with which it shares the same receptor, the EGF receptor (EGFR). Synthesis of TGFalpha and EGFR in reactive astrocytes developing after CNS insults is associated with the differentiative and mitogenic effects of TGFalpha on cultured astrocytes. This suggests a role for TGFalpha in the development of astrogliosis. We evaluated this hypothesis using transgenic mice bearing the human TGFalpha cDNA under the control of the zinc-inducible metallothionein promoter. Expression levels of glial fibrillary acidic protein (GFAP) and vimentin and morphological features of astrocytes were used as indices of astroglial reactivity in adult transgenic versus wild-type mice provided with ZnCl2 in their water for 3 weeks. In the striatum, the hippocampus, and the cervical spinal cord, the three CNS areas monitored, transgenic mice displayed enhanced GFAP mRNA and protein levels and elevated vimentin protein levels. GFAP-immunoreactive astrocytes exhibited numerous thick processes and hypertrophied somata, which are characteristic aspects of reactive astrocytes. Their number increased additionally in the striatum and the spinal cord, but no astrocytic proliferation was observed using bromodeoxyuridine immunohistochemistry. Neither the morphology nor the number of microglial cells appeared modified. A twofold increase in phosphorylated EGFR was detected in the striatum and was associated with the immunohistochemical detection of numerous GFAP-positive astrocytes bearing the EGFR, suggesting a direct action of TGFalpha on astrocytes. Altogether, these results demonstrate that enhanced TGFalpha synthesis is sufficient to trigger astrogliosis throughout the CNS, whereas microglial metabolism is unaffected.

Target dependence of adult neurons: pattern of terminal arborizations.

During development, the survival of neurons in the CNS depends critically on interactions with postsynaptic target cells. The role of target cells on the maintenance of afferent neurons in the adult, however, is a matter of controversy. Morphological alterations of target-deprived neurons, such as axonal retraction or pruning, may occur. We have therefore undertaken an analysis of target-deprived neurons over time after an excitotoxic lesion in order to investigate these potential changes. Dorsal column nuclei (DCN) neurons were deprived of their target neurons in adult rats by the injection of kainic acid into the ventrobasal thalamic complex. Anterogradely transported wheat germ agglutinin conjugated to HRP from the DCN showed a progressive decrease of the density of afferent terminals during the first month after lesion. Density stabilized thereafter through the longest time studied (8 months). In contrast, the extent of the area occupied by DCN projections did not change up to 1 month and then shrank over time. These results indicated a continuous decrease in the number of axonal elements in the lesion, which is the strongest during the first month postlesion. To interpret these data, we then studied axonal morphology. Diffusion-filled lemniscal axons were labeled by WGA-HRP injections aimed at the medial lemniscus. There was no conspicuous alteration of axonal stems in the medial lemniscus. Terminal axonal arborizations and swellings dramatically decreased in number over the first month after the kainate injection, and large axonal varicosities were formed over the same period of time. These morphological data suggest that the decrease in number of axons in an excitotoxic lesion is related, at least during the first month, to a loss of axonal terminal arborizations rather than to a retraction of axonal stems. The pattern of terminal arborizations in the adult CNS may therefore depend critically on interactions of afferents with their target neurons, while the maintenance of the axonal stems does not.