TY - JOUR
T1 - Restoration of Visual Function and Cortical Connectivity After Ischemic Injury Through NeuroD1-Mediated Gene Therapy
AU - Tang, Yu
AU - Wu, Qiuyu
AU - Gao, Mang
AU - Ryu, Esther
AU - Pei, Zifei
AU - Kissinger, Samuel T.
AU - Chen, Yuchen
AU - Rao, Abhinav K.
AU - Xiang, Zongqin
AU - Wang, Tao
AU - Li, Wen
AU - Chen, Gong
AU - Chubykin, Alexander A.
N1 - Funding Information:
We are grateful for financial support from the NIMH grant RF1 MH123401 to AC and Charles H. Smith Endowment Fund to GC.
Publisher Copyright:
© Copyright © 2021 Tang, Wu, Gao, Ryu, Pei, Kissinger, Chen, Rao, Xiang, Wang, Li, Chen and Chubykin.
PY - 2021/8/18
Y1 - 2021/8/18
N2 - 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.
AB - 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.
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U2 - 10.3389/fcell.2021.720078
DO - 10.3389/fcell.2021.720078
M3 - Article
C2 - 34490268
AN - SCOPUS:85114285520
SN - 2296-634X
VL - 9
JO - Frontiers in Cell and Developmental Biology
JF - Frontiers in Cell and Developmental Biology
M1 - 720078
ER -