Upadhya Dinesh, Attaluri Sahithi, Liu Yan, Hattiangady Bharathi, Castro Olagide W, Shuai Bing, Dong Yi, Zhang Su-Chun, Shetty Ashok K
Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine, College Station, TX, USA.
Department of Molecular and Cellular Medicine, Texas A&M Health Science Center College of Medicine, College Station, TX, USA.
NPJ Regen Med. 2022 Aug 1;7(1):38. doi: 10.1038/s41536-022-00234-7.
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.
中间神经元的丧失/功能障碍导致慢性颞叶癫痫（TLE）中的自发性反复癫痫发作（SRS），而将中间神经元移植到癫痫海马体中可减少SRS并改善认知功能。本研究调查了移植来源的γ-氨基丁酸阳性（GABA能）中间神经元是否直接调节慢性TLE大鼠模型中的SRS和认知功能。通过CRISPR/Cas9技术将人多能干细胞来源的内侧神经节隆起样GABA能祖细胞进行工程改造，使其表达hM4D（Gi），这是一种仅由设计药物（DREADDs）激活的设计受体，然后将其移植到慢性癫痫大鼠的海马体中，以便随后使移植来源的中间神经元沉默。这种移植显著减少了SRS并改善了海马体依赖性认知功能。值得注意的是，用设计药物使移植来源的中间神经元沉默会增加SRS并导致位置记忆受损，但不影响模式分离功能。DREADDs的失活恢复了SRS控制和物体位置记忆功能。因此，移植的GABA能中间神经元可直接调节TLE中的SRS和特定认知功能。
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