GABA Antagonism Reduces Sleep Fragmentation and Restores Hourly Sleep in Down Syndrome Model Mice: Pentylenetetrazol as a Therapy for GABAergic Impairment
Abstract/Contents
- Abstract
- Evidence from animal models supports that Down syndrome (DS) is characterized by excessive GABAergic inhibition in the hippocampus and cortex. Treatment with pentylenetetrazol (PTZ), a non-specific GABAA receptor antagonist, rescues memory and long-term potentiation in DS mouse models only if delivered during mice’s inactive phase. This time-dependent effect suggests that GABAergic dysfunction impairs processes specific to the inactive phase, such as those under sleep or circadian control. However, almost no work in DS has explored how excess GABA modulates sleep or the extent to which sleep deficits mediate characteristic delays. That paucity is notable given the degree of sleep impairments—which include high sleep fragmentation, shorter NREM bouts, and reduced REM—and their potential to explain phenotypes in DS. Using a well-characterized DS mouse model, I administer a seventeen-day course of PTZ p.o. to clarify interactions between GABAergic dysfunction, sleep, and cognitive impairment in DS. I show that in model mice, PTZ treatment reduces sleep fragmentation, lengthens NREM bouts, and increases sleep amount over nine zeitgeber hours. These gains persist one-month post treatment. My findings indicate that GABAergic transmission disrupts sleep quality in DS model mice and that sleep represents a modifiable factor among deficits. Sleep offers a potential mechanism for the cognitive and developmental delays born of GABAergic dysfunction. GABA antagonists demand study as pharmacotherapies for sleep and memory in DS.
Description
| Type of resource | text |
|---|---|
| Date modified | December 5, 2022 |
| Publication date | May 5, 2022; May 2022 |
Creators/Contributors
| Author | Artal, Jonathan |
|---|---|
| Thesis advisor | Heller, H. Craig |
| Thesis advisor | Zeitzer, Jamie |
| Degree granting institution | Stanford University, Department of Biology |
Subjects
| Subject | Down syndrome |
|---|---|
| Subject | Sleep |
| Subject | Sleep disorders > Treatment |
| Subject | Sleep-wake cycle |
| Subject | Circadian rhythms |
| Subject | GABA |
| Subject | GABA > Antagonists |
| Subject | Memory |
| Subject | Learning disabilities |
| Subject | Intellectual disability |
| Subject | Pharmacology |
| Genre | Text |
| Genre | Thesis |
Bibliographic information
Access conditions
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 4.0 International license (CC BY-NC).
Preferred citation
- Preferred citation
- Artal, J. and Heller, H. (2023). GABA Antagonism Reduces Sleep Fragmentation and Restores Hourly Sleep in Down Syndrome Model Mice: Pentylenetetrazol as a Therapy for GABAergic Impairment. Stanford Digital Repository. Available at https://purl.stanford.edu/zt319th4206
Collection
Undergraduate Theses, Department of Biology, 2021-2022
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- Contact
- artalj@stanford.edu
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