Grafted hPSC-derived GABA-ergic interneurons regulate seizures and specific cognitive function in temporal lobe
Dinesh Upadhya1,2,3,4, Sahithi Attaluri1,2,3, Yan Liu5
1Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine, College Station, TX, USA.
NPJ Regenerative Medicine
|August 1, 2022
Summary
Transplanted GABA-ergic interneurons reduce seizures and improve memory in epilepsy. Silencing these cells worsened seizures and memory, showing their direct regulatory role in temporal lobe epilepsy.
Area of Science:
- Neuroscience
- Epilepsy Research
- Stem Cell Therapy
Background:
- Interneuron loss/dysfunction in the hippocampus is a key factor in temporal lobe epilepsy (TLE)-related spontaneous recurrent seizures (SRS).
- Grafting interneurons into the epileptic hippocampus has shown promise in reducing SRS and enhancing cognitive function.
Purpose of the Study:
- To investigate the direct regulatory role of transplanted gamma-aminobutyric acid positive (GABA-ergic) interneurons on SRS and cognitive function in a rat model of chronic TLE.
- To utilize CRISPR/Cas9-engineered human pluripotent stem cell-derived GABA-ergic progenitors with DREADDs for controlled manipulation of graft activity.
Main Methods:
- Human pluripotent stem cell-derived medial ganglionic eminence-like GABA-ergic progenitors engineered with DREADDs were grafted into the hippocampi of rats with chronic TLE.
- Graft-derived interneuron activity was silenced using a designer drug, and cognitive functions (location memory, pattern separation) were assessed.
- The impact of silencing and subsequent deactivation of DREADDs on SRS and cognitive function was evaluated.
Main Results:
- Grafting GABA-ergic interneurons significantly reduced SRS and improved hippocampus-dependent cognitive function.
- Silencing of graft-derived interneurons using designer drugs led to increased SRS and impaired location memory, but not pattern separation.
- Deactivation of the DREADDs successfully restored control over SRS and object location memory.
Conclusions:
- Transplanted GABA-ergic interneurons play a direct and critical role in regulating spontaneous recurrent seizures in TLE.
- These grafted interneurons can modulate specific hippocampus-dependent cognitive functions, offering a potential therapeutic avenue.
- The DREADD system provides a valuable tool for precisely controlling the function of transplanted cells in epilepsy models.
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