Hippocampal GAD67 Transduction Using rAAV8 Regulates Epileptogenesis in EL Mice

Molecular Therapy. Methods & Clinical Development
Kuniko ShimazakiTakashi Okada

Abstract

Gene therapy has been employed as a therapeutic approach for intractable focal epilepsies. Considering the potential of focal GABAergic neuromodulation in regulating epileptogenesis, the GABA-producing enzyme, γ-aminobutyric acid decarboxylase 67 (GAD67), is highly suitable for epilepsy therapy. The EL/Suz (EL) mouse is a model of multifactorial temporal lobe epilepsy. In the present study, we examined focal gene transduction in epileptic EL mice using recombinant adeno-associated virus serotype 8 (rAAV8) expressing human GAD67 to enhance GABA-mediated neural inhibition. Eight-week-old mice were bilaterally injected with rAAV8-GFP or rAAV8-GAD67 in the hippocampal CA3 region. After four weeks, the GAD67-transduced EL mice, but not the rAAV-GFP-treated EL mice, exhibited a significant reduction in seizure generation. The GAD67-mediated depression became stable after 14 weeks. The excitability of the CA3 region was markedly reduced in the GAD67-transduced EL mice, consistent with the results of the Ca2+ imaging using hippocampal slices. In addition, downregulation of c-Fos expression was observed in GAD67-transduced hippocampi. Our findings showed that rAAV8-GAD67 induced significant changes in the GABAergic system in the EL hipp...Continue Reading

Citations

Apr 4, 2021·International Journal of Molecular Sciences·Hye Yun KimJae-Ick Kim
Dec 14, 2021·The Journal of Gene Medicine·Keiji OguroShin-Ichi Muramatsu

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Methods Mentioned

BETA
surgical resection
Fluorescence
PCR
transfection
chip
electrophoresis

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