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

Abstract

Brain lesions can unlock a latent neurogenic potential in parenchymal astrocytes. However, the identity of their neuronal progeny has remained unclear. Here, we show that neurons generated by striatal astrocytes following excitotoxic lesions are transient, yet they reach advanced stages of morphological and functional maturation and integrate into cortico-striatal-thalamic circuits. Single-cell RNA-seq mapping onto an embryonic reference revealed that these cells are not related to adult striatal neuron types but instead belong to the LGE-MEIS2/PAX6 interneuron class. Notch abrogation, which mimics neurogenic activation, drives both cortical and striatal astrocytes toward this same interneuron class, revealing a shared intrinsic commitment. In primates, LGE-MEIS2/PAX6 cells transiently populate the embryonic striatum and cortex, and through spatial transcriptomics, we reveal that in mice these cells are also present and widely distributed throughout the telencephalon during embryonic and postnatal development. Thus, unlike other vertebrates in which adult telencephalic astroglia preserve the potential to generate constitutive region-specific neurons, the homologous cells in mammals converge on the generation of a specific transient neuron class, possibly representing a reservoir for circuit plasticity in adult life.