NEUROD1 Instructs Neuronal Conversion in Non-Reactive Astrocytes

Currently, all methods for converting non-neuronal cells into neurons involve injury to the brain; however, whether neuronal transdifferentiation can occur long after the period of insult remains largely unknown. Here, we use the transcription factor NEUROD1, previously shown to convert reactive glial cells to neurons in the cortex, to determine whether astrocyte-to-neuron transdifferentiation can occur under physiological conditions. We utilized adeno-associated virus 9 (AAV9), which crosses the blood-brain barrier without injury, to deliver NEUROD1 to astrocytes through an intravascular route. Interestingly, we found that a small, but significant number of non-reactive astrocytes converted to neurons in the striatum, but not the cortex. Moreover, astrocytes cultured to minimize their proliferative potential also exhibited limited neuronal transdifferentiation with NEUROD1 expression. Our results show that a single transcription factor can induce astrocyte-to-neuron conversion under physiological conditions, potentially facilitating future clinical approaches long after the acute injury phase. •Intravascular AAV9 efficiently targets astrocytes in the cortex and striatum•NEUROD1 can convert a small, but significant number of astrocytes to neurons in vivo•NEUROD1 induces limited neuronal transdifferentiation in vitro•Injury-related factors may be important in neuronal conversion strategies In this article, Hsieh and colleagues use AAV9 viral infection to selectively target and overexpress NEUROD1 in astrocytes in the absence of injury to the CNS. The authors show that NEUROD1 is capable of converting a small, but significant number of astrocytes to neurons in vivo in the absence of reactive gliosis.