The noradrenergic system is necessary for survival of vulnerable midbrain dopaminergic neurons: implications for development and Parkinson's disease

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The cause of midbrain dopaminergic (mDA) neuron loss in sporadic Parkinson's disease (PD) is multifactorial, involving cell autonomous factors, cell-cell interactions, and the effects of environmental toxins. Early loss of neurons in the locus coeruleus (LC), the main source of ascending noradrenergic (NA) projections, is an important feature of PD and other neurodegenerative disorders. We hypothesized that NA afferents provide trophic support for vulnerable mDA neurons. We demonstrate that depriving mDA neurons of NA input increases postnatal apoptosis and decreases cell survival in young adult rodents, with relative sparing of calbindin-positive subpopulations known to be resistant to degeneration in PD. As a mechanism, we propose that the neurotrophin brain-derived neurotrophic factor (BDNF) modulates anterograde survival effects of LC inputs to mDA neurons. We demonstrate that the LC is rich in BDNF mRNA in postnatal and young adult brains. Early postnatal NA denervation reduces both BDNF protein and activation of TrkB receptors in the ventral midbrain. Furthermore, overexpression of BDNF in NA afferents in transgenic mice increases mDA neuronal survival. Finally, increasing NA activity in primary cultures of mDA neurons improves survival, an effect that is additive or synergistic in the presence of different concentrations of BDNF. Taken together, our results point to a novel mechanism whereby LC afferents couple BDNF effects and NA activity to provide anterograde trophic support for vulnerable mDA neurons. Early loss of NA activity and anterograde neurotrophin support may contribute to degeneration of vulnerable neurons in PD and other neurodegenerative disorders.