Brain injury reactivates a developmental program driving genesis and integration of transient LGE-class interneurons

Brain lesions can unlock latent neurogenic potential in parenchymal astrocytes, but the identity of their neuronal progeny has remained unclear. Here, we show that neurons generated by striatal astrocytes after excitotoxic lesions are transient, yet reach advanced morphological and functional maturation and integrate into cortico-striatal-thalamic circuits. Single-cell RNA-seq mapping onto an embryonic reference revealed these cells are not fated to adult striatal neuron types but belong to the LGE-MEIS2/PAX6 interneuron class. Reanalysis of neuroblasts from cortical and striatal astrocytes after Notch abrogation revealed shared commitment of rostral telencephalic astrocytes to this class. Public spatial transcriptomics datasets revealed these cells are widely distributed throughout the mouse telencephalon during embryonic and postnatal development. Thus, unlike other vertebrates in which adult telencephalic astroglia preserve the potential to generate resident, regionally appropriate neuronal types, homologous mammalian cells converge on a specific transient neuron class, possibly representing a reservoir for circuit plasticity in adult life.