Striatal astrocytes transdifferentiate into functional mature neurons following ischemic brain injury

Glia. 2015 Sep;63(9):1660-70. doi: 10.1002/glia.22837. Epub 2015 Jun 1.


To determine whether reactive astrocytes stimulated by brain injury can transdifferentiate into functional new neurons, we labeled these cells by injecting a glial fibrillary acidic protein (GFAP) targeted enhanced green fluorescence protein plasmid (pGfa2-eGFP plasmid) into the striatum of adult rats immediately following a transient middle cerebral artery occlusion (MCAO) and performed immunolabeling with specific neuronal markers to trace the neural fates of eGFP-expressing (GFP(+)) reactive astrocytes. The results showed that a portion of striatal GFP(+) astrocytes could transdifferentiate into immature neurons at 1 week after MCAO and mature neurons at 2 weeks as determined by double staining GFP-expressing cells with βIII-tubulin (GFP(+)-Tuj-1(+)) and microtubule associated protein-2 (GFP(+)-MAP-2(+)), respectively. GFP(+) neurons further expressed choline acetyltransferase, glutamic acid decarboxylase, dopamine receptor D2-like family proteins, and the N-methyl-D-aspartate receptor subunit R2, indicating that astrocyte-derived neurons could develop into cholinergic or GABAergic neurons and express dopamine and glutamate receptors on their membranes. Electron microscopy analysis indicated that GFP(+) neurons could form synapses with other neurons at 13 weeks after MCAO. Electrophysiological recordings revealed that action potentials and active postsynaptic currents could be recorded in the neuron-like GFP(+) cells but not in the astrocyte-like GFP(+) cells, demonstrating that new GFP(+) neurons possessed the capacity to fire action potentials and receive synaptic inputs. These results demonstrated that striatal astrocyte-derived new neurons participate in the rebuilding of functional neural networks, a fundamental basis for brain repair after injury. These results may lead to new therapeutic strategies for enhancing brain repair after ischemic stroke.

Keywords: brain repair; glia; neural network; neurogenesis; stem cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / pathology
  • Astrocytes / physiology*
  • Brain Ischemia / pathology
  • Brain Ischemia / physiopathology*
  • Choline O-Acetyltransferase / metabolism
  • Corpus Striatum / pathology
  • Corpus Striatum / physiopathology*
  • Disease Models, Animal
  • Glial Fibrillary Acidic Protein / genetics
  • Glial Fibrillary Acidic Protein / metabolism
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Infarction, Middle Cerebral Artery
  • Male
  • Microtubule-Associated Proteins / metabolism
  • Neurogenesis / physiology*
  • Neurons / pathology
  • Neurons / physiology*
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D2 / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Stroke / pathology
  • Stroke / physiopathology*
  • Synapses / pathology
  • Synapses / physiology
  • Tissue Culture Techniques
  • Tubulin / metabolism
  • gamma-Aminobutyric Acid / metabolism


  • Glial Fibrillary Acidic Protein
  • MAP2 protein, rat
  • Microtubule-Associated Proteins
  • Receptors, Dopamine D2
  • Receptors, N-Methyl-D-Aspartate
  • Tubb3 protein, rat
  • Tubulin
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • gamma-Aminobutyric Acid
  • Choline O-Acetyltransferase