Developmentally primed cortical neurons maintain fidelity of differentiation and establish appropriate functional connectivity after transplantation

Nat Neurosci. 2018 Apr;21(4):517-529. doi: 10.1038/s41593-018-0098-0. Epub 2018 Mar 5.

Abstract

Repair of complex CNS circuitry requires newly incorporated neurons to become appropriately, functionally integrated. One approach is to direct differentiation of endogenous progenitors in situ, or ex vivo followed by transplantation. Prior studies find that newly incorporated neurons can establish long-distance axon projections, form synapses and functionally integrate in evolutionarily old hypothalamic energy-balance circuitry. We now demonstrate that postnatal neocortical connectivity can be reconstituted with point-to-point precision, including cellular integration of specific, molecularly identified projection neuron subtypes into correct positions, combined with development of appropriate long-distance projections and synapses. Using optogenetics-based electrophysiology, experiments demonstrate functional afferent and efferent integration of transplanted neurons into transcallosal projection neuron circuitry. Results further indicate that 'primed' early postmitotic neurons, including already fate-restricted deep-layer projection neurons and/or plastic postmitotic neuroblasts with partially fate-restricted potential, account for the predominant population of neurons capable of achieving this optimal level of integration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 6-Cyano-7-nitroquinoxaline-2,3-dione / pharmacology
  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Animals
  • Animals, Newborn
  • Cell Adhesion Molecules, Neuronal / metabolism
  • Cell Differentiation / physiology*
  • DNA-Binding Proteins / metabolism
  • Embryo, Mammalian
  • Excitatory Amino Acid Antagonists / pharmacology
  • Gene Expression Regulation, Developmental / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neocortex* / cytology
  • Neocortex* / growth & development
  • Neocortex* / surgery
  • Nerve Tissue Proteins / metabolism
  • Neurons / physiology*
  • Repressor Proteins / metabolism
  • Synaptophysin / metabolism
  • Transcription Factors / metabolism
  • Tumor Suppressor Proteins / metabolism
  • Valine / analogs & derivatives
  • Valine / pharmacology

Substances

  • Bcl11b protein, mouse
  • Cell Adhesion Molecules, Neuronal
  • DNA-Binding Proteins
  • Excitatory Amino Acid Antagonists
  • Nerve Tissue Proteins
  • Repressor Proteins
  • Stab2 protein, mouse
  • Synaptophysin
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Zfp312 protein, mouse
  • Zfpm2 protein, mouse
  • 6-Cyano-7-nitroquinoxaline-2,3-dione
  • 2-amino-5-phosphopentanoic acid
  • Valine