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In vivo reprogramming of circuit connectivity in postmitotic neocortical neurons.
The molecular mechanisms that control how progenitors generate distinct subtypes of neurons, and how undifferentiated neurons acquire their specific identity during corticogenesis, are increasingly understood. However, whether postmitotic neurons can change their identity at late stages of differentiation remains unknown. To study this question, we developed an electrochemical in vivo gene delivery method to rapidly manipulate gene expression specifically in postmitotic neurons. Using this approach, we found that the molecular identity, morphology, physiology and functional input-output connectivity of layer 4 mouse spiny neurons could be specifically reprogrammed during the first postnatal week by ectopic expression of the layer 5B output neuron-specific transcription factor Fezf2. These findings reveal a high degree of plasticity in the identity of postmitotic neocortical neurons and provide a proof of principle for postnatal re-engineering of specific neural microcircuits in vivo.
Age Factors, Animals, Animals, Newborn, Cell Cycle/drug effects, Cell Cycle/genetics, Cholera Toxin/metabolism, Cyclohexanones/pharmacology, DNA-Binding Proteins/genetics, DNA-Binding Proteins/metabolism, Dendrites/metabolism, Embryo, Mammalian, Epithelial Sodium Channels/genetics, Gene Expression Regulation, Developmental/drug effects, Gene Expression Regulation, Developmental/genetics, Green Fluorescent Proteins/genetics, Membrane Potentials/drug effects, Membrane Potentials/genetics, Mice, Mice, Transgenic, Microscopy, Electron, Transmission, Neocortex/cytology, Neocortex/embryology, Nerve Net/physiology, Nerve Tissue Proteins/genetics, Nerve Tissue Proteins/metabolism, Neural Pathways/physiology, Neurons/physiology, Neurons/ultrastructure, Patch-Clamp Techniques, Rhodopsin/genetics, Statistics, Nonparametric, Vesicular Glutamate Transport Protein 2/metabolism
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