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

The cytokine tumour necrosis factor-alpha (TNFalpha) 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 TNFalpha on embryonic dopaminergic neurons of the ventral mesencephalon. TNFalpha 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 TNFalpha signalled via NF-kappaB. This enhancement in cell number was found to be due to TNFalpha promoting the differentiation of dopaminergic neurons rather than to an increase in cell survival. In contrast, TNFalpha-treated cultures derived from E14 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 TNFalpha from neurotrophic to neurotoxic. This is the first report of a population of neurons exhibiting this switch in TNFalpha responsiveness during neurodevelopment.