TY - JOUR
T1 - Grafted hPSC-derived GABA-ergic interneurons regulate seizures and specific cognitive function in temporal lobe epilepsy
AU - Upadhya, Dinesh
AU - Attaluri, Sahithi
AU - Liu, Yan
AU - Hattiangady, Bharathi
AU - Castro, Olagide W.
AU - Shuai, Bing
AU - Dong, Yi
AU - Zhang, Su Chun
AU - Shetty, Ashok K.
N1 - Funding Information:
This work was supported by grants from the Department of Defense (W81XWH-14-1-0558 to A.K.S.), the Department of Veterans Affairs (Merit Award I01BX000883 and BLR&D Research Career Scientist award 1IK6BX003612 to A.K.S.), and the National Institutes of Health (R01 NS106907 to A.K.S., and R01 NS086604, R01 NS096282 and R01 MH100031 to S.-C.Z.).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Interneuron loss/dysfunction contributes to spontaneous recurrent seizures (SRS) in chronic temporal lobe epilepsy (TLE), and interneuron grafting into the epileptic hippocampus reduces SRS and improves cognitive function. This study investigated whether graft-derived gamma-aminobutyric acid positive (GABA-ergic) interneurons directly regulate SRS and cognitive function in a rat model of chronic TLE. Human pluripotent stem cell-derived medial ganglionic eminence-like GABA-ergic progenitors, engineered to express hM4D(Gi), a designer receptor exclusively activated by designer drugs (DREADDs) through CRISPR/Cas9 technology, were grafted into hippocampi of chronically epileptic rats to facilitate the subsequent silencing of graft-derived interneurons. Such grafting substantially reduced SRS and improved hippocampus-dependent cognitive function. Remarkably, silencing of graft-derived interneurons with a designer drug increased SRS and induced location memory impairment but did not affect pattern separation function. Deactivation of DREADDs restored both SRS control and object location memory function. Thus, transplanted GABA-ergic interneurons could directly regulate SRS and specific cognitive functions in TLE.
AB - Interneuron loss/dysfunction contributes to spontaneous recurrent seizures (SRS) in chronic temporal lobe epilepsy (TLE), and interneuron grafting into the epileptic hippocampus reduces SRS and improves cognitive function. This study investigated whether graft-derived gamma-aminobutyric acid positive (GABA-ergic) interneurons directly regulate SRS and cognitive function in a rat model of chronic TLE. Human pluripotent stem cell-derived medial ganglionic eminence-like GABA-ergic progenitors, engineered to express hM4D(Gi), a designer receptor exclusively activated by designer drugs (DREADDs) through CRISPR/Cas9 technology, were grafted into hippocampi of chronically epileptic rats to facilitate the subsequent silencing of graft-derived interneurons. Such grafting substantially reduced SRS and improved hippocampus-dependent cognitive function. Remarkably, silencing of graft-derived interneurons with a designer drug increased SRS and induced location memory impairment but did not affect pattern separation function. Deactivation of DREADDs restored both SRS control and object location memory function. Thus, transplanted GABA-ergic interneurons could directly regulate SRS and specific cognitive functions in TLE.
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U2 - 10.1038/s41536-022-00234-7
DO - 10.1038/s41536-022-00234-7
M3 - Article
AN - SCOPUS:85135216228
SN - 2057-3995
VL - 7
JO - npj Regenerative Medicine
JF - npj Regenerative Medicine
IS - 1
M1 - 38
ER -