title: Striatal astrocytes transdifferentiate into functional mature neurons following ischemic brain injury.
abstract: 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.
authors.affiliation: Department of Neurobiology, School of Basic Medical Science, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.|Research Unit of Brain Injury, State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
authors.forename: Chun-Ling
authors.initials: CL
authors.lastname: Duan
authors.affiliation: Department of Neurobiology, School of Basic Medical Science, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.|Research Unit of Brain Injury, State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
authors.forename: Chong-Wei
authors.initials: CW
authors.lastname: Liu
authors.affiliation: Department of Neurobiology, School of Basic Medical Science, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.|Research Unit of Brain Injury, State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
authors.forename: Shu-Wen
authors.initials: SW
authors.lastname: Shen
authors.affiliation: The Electron Microscopy Core Laboratory, School of Basic Medical Science, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Neurobiology, School of Basic Medical Science, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.|Research Unit of Brain Injury, State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.|Research Institute of Aging Biology, Research Center on Aging and Medicine and Institutes for Biomedical Science, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
authors.forename: Jia-Lin
authors.initials: JL
authors.lastname: Mo
authors.affiliation: Department of Neurobiology, School of Basic Medical Science, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.|Research Unit of Brain Injury, State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
authors.forename: Xian-Hua
authors.initials: XH
authors.lastname: Chen
authors.affiliation: Department of Neurobiology, School of Basic Medical Science, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.|Research Unit of Brain Injury, State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.|Research Institute of Aging Biology, Research Center on Aging and Medicine and Institutes for Biomedical Science, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
authors.forename: Feng-Yan
authors.initials: FY
authors.lastname: Sun
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000473:pathology / Q000502:physiology*; D002545:Brain Ischemia / Q000473:pathology / Q000503:physiopathology*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003342:Corpus Striatum / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D020521:Stroke / Q000473:pathology / Q000503:physiopathology*; D013569:Synapses / Q000473:pathology / Q000502:physiology; D046509:Tissue Culture Techniques; D014404:Tubulin / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D017448:Receptors, Dopamine D2; D016194:Receptors, N-Methyl-D-Aspartate; C488416:Tubb3 protein, rat; D014404:Tubulin; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D005680:gamma-Aminobutyric Acid; D002795:Choline O-Acetyltransferase
keywords: brain repair; glia; neural network; neurogenesis; stem cell