J. Neurochem. (2011) 117, 1066–1074. Abstract Neuregulin‐1 (Nrg1) is genetically linked to schizophrenia, a disease caused by neurodevelopmental imbalance in dopaminergic function. The Nrg1 receptor ErbB4 is abundantly expressed on midbrain dopaminergic neurons. Nrg1 has been shown to penetrate blood‐brain barrier, and peripherally administered Nrg1 activates ErbB4 and leads to a persistent hyperdopaminergic state in neonatal mice. These data prompted us to study the effect of peripheral administration of Nrg1 in the context of Parkinson’s disease, a neurodegenerative disorder affecting the dopaminergic system in the adult brain. We observed that systemic injections of the extracellular domain of Nrg1β1 (Nrg1β1‐ECD) increased dopamine levels in the substantia nigra and striatum of adult mice. Nrg1β1‐ECD injections also significantly protected the mouse nigrostriatal dopaminergic system morphologically and functionally against 6‐hydroxydopamine‐induced toxicity in vivo. Moreover, Nrg1β1‐ECD also protected human dopaminergic neurons in vitro against 6‐hydroxydopamine. In conclusion, we have identified Nrg1β1‐ECD as a neurotrophic factor for adult mouse and human midbrain dopaminergic neurons with peripheral administratability, warranting further investigation as therapeutic option for Parkinson’s disease patients.

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