Abstract:Brain injury results in loss of neurons and activation of glial cells,a phenomenon called reactive gliosis.Gliosis is also widely associated with spinal cord injury,stroke,glioma,and neurodegenerative disorders such as Alzheimers disease(AD).Currently,there is no effective way to reverse gliosis after brain injury or neurodegeneration.We injected retrovirus encoding a single neural transcription factor NeuroD1 into adult mouse cortex to convert reactive glial cells into functional neurons,which were immunopositive for neuronal markers DCX,Tuj1 and NeuN.Using astrocytic promoter GFAP or NG2 promoter to drive NeuroD1 expression,we demonstrated that both astrocytes and NG2 cells were converted into neurons in vivo and in vitro.Cortical slice recordings revealed both spontaneous and evoked synaptic responses in NeuroD1-converted neurons,suggesting the integration of converted neurons into local neural circuits.Using a transgenic mouse model for AD(5xFAD mice),we demonstrated that NeuroD1 converted reactive glial cells into functional neurons in 7-14 months old AD mice.Moreover,NeuroD1 also converted cultured human astrocytes into functional neurons.Our studies demonstrate the proof-of-concept that converting reactive glial cells into functional neurons in injured or diseased brain may provide a potential new therapy for brain repair.