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Level of hM4D(Gi) DREADD expression determines inhibitory and neurotoxic effects in the hippocampus

Marie-Gabrielle Goossens, Lars Emil Larsen (UGent) , Marijke Vergaelen (UGent) , Wytse Wadman (UGent) , Chris Van den Haute, Wayra Brackx (UGent) , Silke Proesmans, Jana Desloovere, Emma Christiaen, Erine Craey, et al.
(2021) ENEURO. 8(6).
Author
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Abstract
Selective neuromodulation using designer receptors exclusively activated by designer drugs (DREADDs) has become an increasingly important research tool, as well as an emerging therapeutic approach. However, the safety profile of DREADD expression is unknown. Here, different titers of adeno-associated viral (AAV) vector were administered in an attempt to vary total expression levels of the inhibitory DREADD hM4D(Gi) in excitatory hippocampal neurons. Male Sprague Dawley rats were injected with AAV2/7 encoding DREADD-mCherry, DREADD, or mCherry. Pronounced neuronal loss and neuroinflammatory reactions were observed after transduction with the high titer DREADD AAV, which also resulted in the highest DREADD expression levels. No such effects were observed in the mCherry control group, despite an equally high titer, nor in conditions where lower viral vector titers were injected. In the high titer DREADD conditions, dentate gyrus (DG) evoked potentials were inhibited on clozapine-induced activation of hM4D(Gi), while in low titer conditions DG evoked potentials were enhanced. Recordings of single neuronal activity nevertheless indicated a reduction in spontaneous firing of granule cell layer neurons. Our results indicate that prolonged, high levels of DREADD expression can have neurotoxic effects and that chemogenetic suppression of excitatory hippocampal neurons can paradoxically enhance DG evoked potentials.
Keywords
chemogenetics, DREADD, hippocampus, neurotoxicity, rat, viral vector, ADENOASSOCIATED VIRUS VECTOR, NEURONS, PROTEIN, ACTIVATION, TOXICITY, OVEREXPRESSION, PLATFORM, PATHWAY, SYSTEM, CELLS

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MLA
Goossens, Marie-Gabrielle, et al. “Level of HM4D(Gi) DREADD Expression Determines Inhibitory and Neurotoxic Effects in the Hippocampus.” ENEURO, vol. 8, no. 6, 2021, doi:10.1523/eneuro.0105-21.2021.
APA
Goossens, M.-G., Larsen, L. E., Vergaelen, M., Wadman, W., Van den Haute, C., Brackx, W., … Raedt, R. (2021). Level of hM4D(Gi) DREADD expression determines inhibitory and neurotoxic effects in the hippocampus. ENEURO, 8(6). https://doi.org/10.1523/eneuro.0105-21.2021
Chicago author-date
Goossens, Marie-Gabrielle, Lars Emil Larsen, Marijke Vergaelen, Wytse Wadman, Chris Van den Haute, Wayra Brackx, Silke Proesmans, et al. 2021. “Level of HM4D(Gi) DREADD Expression Determines Inhibitory and Neurotoxic Effects in the Hippocampus.” ENEURO 8 (6). https://doi.org/10.1523/eneuro.0105-21.2021.
Chicago author-date (all authors)
Goossens, Marie-Gabrielle, Lars Emil Larsen, Marijke Vergaelen, Wytse Wadman, Chris Van den Haute, Wayra Brackx, Silke Proesmans, Jana Desloovere, Emma Christiaen, Erine Craey, Christian Vanhove, Kristl Vonck, Paul Boon, and Robrecht Raedt. 2021. “Level of HM4D(Gi) DREADD Expression Determines Inhibitory and Neurotoxic Effects in the Hippocampus.” ENEURO 8 (6). doi:10.1523/eneuro.0105-21.2021.
Vancouver
1.
Goossens M-G, Larsen LE, Vergaelen M, Wadman W, Van den Haute C, Brackx W, et al. Level of hM4D(Gi) DREADD expression determines inhibitory and neurotoxic effects in the hippocampus. ENEURO. 2021;8(6).
IEEE
[1]
M.-G. Goossens et al., “Level of hM4D(Gi) DREADD expression determines inhibitory and neurotoxic effects in the hippocampus,” ENEURO, vol. 8, no. 6, 2021.
@article{8724128,
  abstract     = {{Selective neuromodulation using designer receptors exclusively activated by designer drugs (DREADDs) has become an increasingly important research tool, as well as an emerging therapeutic approach. However, the safety profile of DREADD expression is unknown. Here, different titers of adeno-associated viral (AAV) vector were administered in an attempt to vary total expression levels of the inhibitory DREADD hM4D(Gi) in excitatory hippocampal neurons. Male Sprague Dawley rats were injected with AAV2/7 encoding DREADD-mCherry, DREADD, or mCherry. Pronounced neuronal loss and neuroinflammatory reactions were observed after transduction with the high titer DREADD AAV, which also resulted in the highest DREADD expression levels. No such effects were observed in the mCherry control group, despite an equally high titer, nor in conditions where lower viral vector titers were injected. In the high titer DREADD conditions, dentate gyrus (DG) evoked potentials were inhibited on clozapine-induced activation of hM4D(Gi), while in low titer conditions DG evoked potentials were enhanced. Recordings of single neuronal activity nevertheless indicated a reduction in spontaneous firing of granule cell layer neurons. Our results indicate that prolonged, high levels of DREADD expression can have neurotoxic effects and that chemogenetic suppression of excitatory hippocampal neurons can paradoxically enhance DG evoked potentials.}},
  articleno    = {{0105-21.2021}},
  author       = {{Goossens, Marie-Gabrielle and Larsen, Lars Emil and Vergaelen, Marijke and Wadman, Wytse and Van den Haute, Chris and Brackx, Wayra and Proesmans, Silke and Desloovere, Jana and Christiaen, Emma and Craey, Erine and Vanhove, Christian and Vonck, Kristl and Boon, Paul and Raedt, Robrecht}},
  issn         = {{2373-2822}},
  journal      = {{ENEURO}},
  keywords     = {{chemogenetics,DREADD,hippocampus,neurotoxicity,rat,viral vector,ADENOASSOCIATED VIRUS VECTOR,NEURONS,PROTEIN,ACTIVATION,TOXICITY,OVEREXPRESSION,PLATFORM,PATHWAY,SYSTEM,CELLS}},
  language     = {{eng}},
  number       = {{6}},
  pages        = {{16}},
  title        = {{Level of hM4D(Gi) DREADD expression determines inhibitory and neurotoxic effects in the hippocampus}},
  url          = {{http://doi.org/10.1523/eneuro.0105-21.2021}},
  volume       = {{8}},
  year         = {{2021}},
}
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