Cargando…

Restoration of Visual Function and Cortical Connectivity After Ischemic Injury Through NeuroD1-Mediated Gene Therapy

Neural circuits underlying brain functions are vulnerable to damage, including ischemic injury, leading to neuronal loss and gliosis. Recent technology of direct conversion of endogenous astrocytes into neurons in situ can simultaneously replenish the neuronal population and reverse the glial scar....

Descripción completa

Detalles Bibliográficos
Autores principales: Tang, Yu, Wu, Qiuyu, Gao, Mang, Ryu, Esther, Pei, Zifei, Kissinger, Samuel T., Chen, Yuchen, Rao, Abhinav K., Xiang, Zongqin, Wang, Tao, Li, Wen, Chen, Gong, Chubykin, Alexander A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416524/
https://www.ncbi.nlm.nih.gov/pubmed/34490268
http://dx.doi.org/10.3389/fcell.2021.720078
_version_ 1783748202383540224
author Tang, Yu
Wu, Qiuyu
Gao, Mang
Ryu, Esther
Pei, Zifei
Kissinger, Samuel T.
Chen, Yuchen
Rao, Abhinav K.
Xiang, Zongqin
Wang, Tao
Li, Wen
Chen, Gong
Chubykin, Alexander A.
author_facet Tang, Yu
Wu, Qiuyu
Gao, Mang
Ryu, Esther
Pei, Zifei
Kissinger, Samuel T.
Chen, Yuchen
Rao, Abhinav K.
Xiang, Zongqin
Wang, Tao
Li, Wen
Chen, Gong
Chubykin, Alexander A.
author_sort Tang, Yu
collection PubMed
description Neural circuits underlying brain functions are vulnerable to damage, including ischemic injury, leading to neuronal loss and gliosis. Recent technology of direct conversion of endogenous astrocytes into neurons in situ can simultaneously replenish the neuronal population and reverse the glial scar. However, whether these newly reprogrammed neurons undergo normal development, integrate into the existing neuronal circuit, and acquire functional properties specific for this circuit is not known. We investigated the effect of NeuroD1-mediated in vivo direct reprogramming on visual cortical circuit integration and functional recovery in a mouse model of ischemic injury. After performing electrophysiological extracellular recordings and two-photon calcium imaging of reprogrammed cells in vivo and mapping the synaptic connections formed onto these cells ex vivo, we discovered that NeuroD1 reprogrammed neurons were integrated into the cortical microcircuit and acquired direct visual responses. Furthermore, following visual experience, the reprogrammed neurons demonstrated maturation of orientation selectivity and functional connectivity. Our results show that NeuroD1-reprogrammed neurons can successfully develop and integrate into the visual cortical circuit leading to vision recovery after ischemic injury.
format Online
Article
Text
id pubmed-8416524
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-84165242021-09-05 Restoration of Visual Function and Cortical Connectivity After Ischemic Injury Through NeuroD1-Mediated Gene Therapy Tang, Yu Wu, Qiuyu Gao, Mang Ryu, Esther Pei, Zifei Kissinger, Samuel T. Chen, Yuchen Rao, Abhinav K. Xiang, Zongqin Wang, Tao Li, Wen Chen, Gong Chubykin, Alexander A. Front Cell Dev Biol Cell and Developmental Biology Neural circuits underlying brain functions are vulnerable to damage, including ischemic injury, leading to neuronal loss and gliosis. Recent technology of direct conversion of endogenous astrocytes into neurons in situ can simultaneously replenish the neuronal population and reverse the glial scar. However, whether these newly reprogrammed neurons undergo normal development, integrate into the existing neuronal circuit, and acquire functional properties specific for this circuit is not known. We investigated the effect of NeuroD1-mediated in vivo direct reprogramming on visual cortical circuit integration and functional recovery in a mouse model of ischemic injury. After performing electrophysiological extracellular recordings and two-photon calcium imaging of reprogrammed cells in vivo and mapping the synaptic connections formed onto these cells ex vivo, we discovered that NeuroD1 reprogrammed neurons were integrated into the cortical microcircuit and acquired direct visual responses. Furthermore, following visual experience, the reprogrammed neurons demonstrated maturation of orientation selectivity and functional connectivity. Our results show that NeuroD1-reprogrammed neurons can successfully develop and integrate into the visual cortical circuit leading to vision recovery after ischemic injury. Frontiers Media S.A. 2021-08-18 /pmc/articles/PMC8416524/ /pubmed/34490268 http://dx.doi.org/10.3389/fcell.2021.720078 Text en Copyright © 2021 Tang, Wu, Gao, Ryu, Pei, Kissinger, Chen, Rao, Xiang, Wang, Li, Chen and Chubykin. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Tang, Yu
Wu, Qiuyu
Gao, Mang
Ryu, Esther
Pei, Zifei
Kissinger, Samuel T.
Chen, Yuchen
Rao, Abhinav K.
Xiang, Zongqin
Wang, Tao
Li, Wen
Chen, Gong
Chubykin, Alexander A.
Restoration of Visual Function and Cortical Connectivity After Ischemic Injury Through NeuroD1-Mediated Gene Therapy
title Restoration of Visual Function and Cortical Connectivity After Ischemic Injury Through NeuroD1-Mediated Gene Therapy
title_full Restoration of Visual Function and Cortical Connectivity After Ischemic Injury Through NeuroD1-Mediated Gene Therapy
title_fullStr Restoration of Visual Function and Cortical Connectivity After Ischemic Injury Through NeuroD1-Mediated Gene Therapy
title_full_unstemmed Restoration of Visual Function and Cortical Connectivity After Ischemic Injury Through NeuroD1-Mediated Gene Therapy
title_short Restoration of Visual Function and Cortical Connectivity After Ischemic Injury Through NeuroD1-Mediated Gene Therapy
title_sort restoration of visual function and cortical connectivity after ischemic injury through neurod1-mediated gene therapy
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416524/
https://www.ncbi.nlm.nih.gov/pubmed/34490268
http://dx.doi.org/10.3389/fcell.2021.720078
work_keys_str_mv AT tangyu restorationofvisualfunctionandcorticalconnectivityafterischemicinjurythroughneurod1mediatedgenetherapy
AT wuqiuyu restorationofvisualfunctionandcorticalconnectivityafterischemicinjurythroughneurod1mediatedgenetherapy
AT gaomang restorationofvisualfunctionandcorticalconnectivityafterischemicinjurythroughneurod1mediatedgenetherapy
AT ryuesther restorationofvisualfunctionandcorticalconnectivityafterischemicinjurythroughneurod1mediatedgenetherapy
AT peizifei restorationofvisualfunctionandcorticalconnectivityafterischemicinjurythroughneurod1mediatedgenetherapy
AT kissingersamuelt restorationofvisualfunctionandcorticalconnectivityafterischemicinjurythroughneurod1mediatedgenetherapy
AT chenyuchen restorationofvisualfunctionandcorticalconnectivityafterischemicinjurythroughneurod1mediatedgenetherapy
AT raoabhinavk restorationofvisualfunctionandcorticalconnectivityafterischemicinjurythroughneurod1mediatedgenetherapy
AT xiangzongqin restorationofvisualfunctionandcorticalconnectivityafterischemicinjurythroughneurod1mediatedgenetherapy
AT wangtao restorationofvisualfunctionandcorticalconnectivityafterischemicinjurythroughneurod1mediatedgenetherapy
AT liwen restorationofvisualfunctionandcorticalconnectivityafterischemicinjurythroughneurod1mediatedgenetherapy
AT chengong restorationofvisualfunctionandcorticalconnectivityafterischemicinjurythroughneurod1mediatedgenetherapy
AT chubykinalexandera restorationofvisualfunctionandcorticalconnectivityafterischemicinjurythroughneurod1mediatedgenetherapy