CRISPR-based epigenetic editing of Gad1 improves synaptic inhibition and cognitive behavior in a Tauopathy mouse model
GABAergic signaling in the brain plays a key role in regulating synaptic transmission, neuronal excitability, and cognitive processes. Large-scale sequencing has revealed the diminished expression of GABA-related genes in Alzheimer's disease (AD), however, it is largely unclear about the epigen...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-03-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125000427 |
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| author | Lei Wan Ping Zhong Pei Li Yong Ren Wei Wang Mingjun Yu Henry Y. Feng Zhen Yan |
| author_facet | Lei Wan Ping Zhong Pei Li Yong Ren Wei Wang Mingjun Yu Henry Y. Feng Zhen Yan |
| author_sort | Lei Wan |
| collection | DOAJ |
| description | GABAergic signaling in the brain plays a key role in regulating synaptic transmission, neuronal excitability, and cognitive processes. Large-scale sequencing has revealed the diminished expression of GABA-related genes in Alzheimer's disease (AD), however, it is largely unclear about the epigenetic mechanisms that dysregulate the transcription of these genes in AD. We confirmed that GABA synthesizing enzymes, GAD1 and GAD2, were significantly downregulated in prefrontal cortex (PFC) of AD human postmortem tissues. A tauopathy mouse model also had the significantly reduced expression of GABA-related genes, as well as the diminished GABAergic synaptic transmission in PFC pyramidal neurons. To elevate endogenous Gad1 levels, we used the CRISPR/Cas9-based epigenome editing technology to recruit histone acetyltransferase p300 to Gad1. Cells transfected with a fusion protein consisting of the nuclease-null dCas9 protein and the catalytic core of p300 (dCas9p300), as well as a guide RNA targeting Gad1 promoter (gRNAGad1), had significantly increased Gad1 mRNA expression and histone acetylation at Gad1 promoter. Furthermore, the tauopathy mouse model with PFC injection of dCas9p300 and gRNAGad1 lentiviruses had significantly elevated GABAergic synaptic currents and improved spatial memory. These results have provided an epigenetic editing-based gene-targeting strategy to restore synaptic inhibition and cognitive function in AD and related disorders. |
| format | Article |
| id | doaj-art-66259939599849648c963f8611bd309f |
| institution | Kabale University |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-66259939599849648c963f8611bd309f2025-02-04T04:10:18ZengElsevierNeurobiology of Disease1095-953X2025-03-01206106826CRISPR-based epigenetic editing of Gad1 improves synaptic inhibition and cognitive behavior in a Tauopathy mouse modelLei Wan0Ping Zhong1Pei Li2Yong Ren3Wei Wang4Mingjun Yu5Henry Y. Feng6Zhen Yan7Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214, USADepartment of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214, USADepartment of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214, USADepartment of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214, USADepartment of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214, USADepartment of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214, USADepartment of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214, USACorresponding author at: State University of New York at Buffalo, 955 Main St., Buffalo, NY, USA.; Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214, USAGABAergic signaling in the brain plays a key role in regulating synaptic transmission, neuronal excitability, and cognitive processes. Large-scale sequencing has revealed the diminished expression of GABA-related genes in Alzheimer's disease (AD), however, it is largely unclear about the epigenetic mechanisms that dysregulate the transcription of these genes in AD. We confirmed that GABA synthesizing enzymes, GAD1 and GAD2, were significantly downregulated in prefrontal cortex (PFC) of AD human postmortem tissues. A tauopathy mouse model also had the significantly reduced expression of GABA-related genes, as well as the diminished GABAergic synaptic transmission in PFC pyramidal neurons. To elevate endogenous Gad1 levels, we used the CRISPR/Cas9-based epigenome editing technology to recruit histone acetyltransferase p300 to Gad1. Cells transfected with a fusion protein consisting of the nuclease-null dCas9 protein and the catalytic core of p300 (dCas9p300), as well as a guide RNA targeting Gad1 promoter (gRNAGad1), had significantly increased Gad1 mRNA expression and histone acetylation at Gad1 promoter. Furthermore, the tauopathy mouse model with PFC injection of dCas9p300 and gRNAGad1 lentiviruses had significantly elevated GABAergic synaptic currents and improved spatial memory. These results have provided an epigenetic editing-based gene-targeting strategy to restore synaptic inhibition and cognitive function in AD and related disorders.http://www.sciencedirect.com/science/article/pii/S0969996125000427Alzheimer's diseaseGABAergic transmissionGAD1Histone acetylationCRISPRPrefrontal cortex |
| spellingShingle | Lei Wan Ping Zhong Pei Li Yong Ren Wei Wang Mingjun Yu Henry Y. Feng Zhen Yan CRISPR-based epigenetic editing of Gad1 improves synaptic inhibition and cognitive behavior in a Tauopathy mouse model Neurobiology of Disease Alzheimer's disease GABAergic transmission GAD1 Histone acetylation CRISPR Prefrontal cortex |
| title | CRISPR-based epigenetic editing of Gad1 improves synaptic inhibition and cognitive behavior in a Tauopathy mouse model |
| title_full | CRISPR-based epigenetic editing of Gad1 improves synaptic inhibition and cognitive behavior in a Tauopathy mouse model |
| title_fullStr | CRISPR-based epigenetic editing of Gad1 improves synaptic inhibition and cognitive behavior in a Tauopathy mouse model |
| title_full_unstemmed | CRISPR-based epigenetic editing of Gad1 improves synaptic inhibition and cognitive behavior in a Tauopathy mouse model |
| title_short | CRISPR-based epigenetic editing of Gad1 improves synaptic inhibition and cognitive behavior in a Tauopathy mouse model |
| title_sort | crispr based epigenetic editing of gad1 improves synaptic inhibition and cognitive behavior in a tauopathy mouse model |
| topic | Alzheimer's disease GABAergic transmission GAD1 Histone acetylation CRISPR Prefrontal cortex |
| url | http://www.sciencedirect.com/science/article/pii/S0969996125000427 |
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