Developmental switch in the effects of TNFα on ventral midbrain dopaminergic neurons

The cytokine tumour necrosis factor-alpha (TNF alpha) has been implicated in the pathogenesis of neurodegenerative conditions as well as in the establishment of neural networks during development. This study investigated the in vitro effects of TNF alpha on embryonic dopaminergic neurons of the ventral mesencephalon. TNF alpha treatment enhanced the number of dopaminergic neurons in cultures derived from E12.5 mice embryos in a dose-dependent manner. In order to achieve this effect TNF alpha signalled via NF-kappa B. This enhancement in cell number was found to be due to TNF alpha promoting the differentiation of dopaminergic neurons rather than to an increase in cell survival. In contrast, TNF alpha-treated cultures derived from E 14 or E16 mice demonstrated a decrease in dopaminergic neurons, and this loss was negated by pharmacological inhibition of caspases. The data presented demonstrate that during embryonic development, dopaminergic ventral mesencephalic neurons switch their in vitro response to TNF alpha from neurotrophic to neurotoxic. This is the first report of a population of neurons exhibiting this switch in TNF alpha responsiveness during neurodevelopment. (c) 2006 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.