Reducing Gabaergic Inhibition Restores Cognitive Functions in a Mouse Model of Down Syndrome
Open accessAbstract
Alterations in excitatory-inhibitory balance occur in Down syndrome and could be responsible for cognitive deficits observed through the life of all individuals carrying an extra copy of chromosome 21. Excess of inhibition in the adult could produce synaptic plasticity deficits that may be a primary mechanism contributing to learning and memory impairments. In this study we discuss pharmacological treatments that could potentially alleviate neuronal inhibition and have been tested in a mouse model of Down syndrome. γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mature central nervous system that binds to GABA-benzodiazepine receptors, opens a chloride channel and reduces neuronal excitability. These receptors have been extensively studied as targets for treatment of epilepsy, anxiety, sleep, cognitive disorders and the induction of sedation. Molecules that are either antagonists or inverse agonists of the GABA-benzodiazepine receptors are able to reduce inhibitory GABAergic transmission. However modulating the excitatory-inhibitory balance towards increase of cognition without inducing seizures remains difficult particularly when using GABA antagonists. In this study we review data from the literature obtained using inverse agonists selective for the α5-subunit containing receptor. Such inverse agonists, initially developed as cognitive enhancers for treatment of memory impairments, proved to be very efficient in reversing learning and memory deficits in a Down syndrome mouse model after acute treatment.
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The reduced capacity for long-term potentiation in Ts65Dn animals is driven by increased GABAergic neurotransmission, and pharmacological reduction of GABAergic neurotransmission is sufficient to rescue this long-term potentiation phenotype.
“The reduced capacity for LTP is driven by increased GABAergic neurotransmission in these animals, and pharmacological reduction of GABAergic neurotransmission is sufficient to rescue this LTP phenotype127–129.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [129]
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References 64 · Cited by 34
- Authors
- Potier, M.-C., Braudeau, J., Dauphinot, L., & Delatour, B.
- Affiliations
- Institut du Cerveau (FR)
- ORCID
- Potier, Marie-Claude
- Venue
- CNS & Neurological Disorders - Drug Targets
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2014-02
- Volume
- 13
- Issue
- 1
- Pages
- 8-15
- ISSN
- 1568-007X (ISSN-L)
- 1871-5273
- OpenAlex
- W2097474499
- Cited by
- 34
- References
- 64
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 3 · 2022: 4 · 2021: 1 · 2020: 1 · 2019: 3 · 2018: 2 · 2017: 4 · 2016: 3 · 2015: 3 · 2014: 3
- FWCI
- 4.29
- Type
- journal article
- Language
- en
- Open access
- green
- cnrs.hal.science
- Licence
- other-oa
- Locations
- CNS & Neurological Disorders - Drug Targets (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- Down syndrome, GABAergic inhibition, excitation-inhibition balance, GABA-benzodiazepine receptor complex, cognitive impairment, learning and memory impairment, pharmacotherapy
- MeSH terms
- Animals, Cognition Disorders, Disease Models, Animal, Down Syndrome, gamma-Aminobutyric Acid, Humans, Receptors, GABA, GABA Agents, Mice
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