Effects of membrane cholesterol on the sensitivity of the GABAA receptor to GABA in acutely dissociated rat hippocampal neurones
Abstract
The effects of membrane cholesterol on the GABA(A) receptor were investigated in acutely dissociated rat hippocampal neurones, using the whole-cell patch clamp technique. Neuronal cholesterol was manipulated within the range 56-250% control by incubation with methyl-beta-cyclodextrin for depletion and a complex of cholesterol and methyl-beta-cyclodextrin for enrichment. Manipulation over a narrower range was achieved with cholesterol + phosphatidylcholine liposomes. A complex of epicholesterol and methyl-beta-cyclodextrin was used to insert epicholesterol. Cholesterol enrichment reduced the potency of GABA, as did cholesterol depletion, with increases in EC(50) of up to 4-fold. Cholesterol enrichment reduced the potency of the competitive antagonist bicuculline but did not affect that of the non-competitive antagonist picrotoxinin. Cholesterol depletion did not affect the potencies of either antagonist. Epicholesterol substituted functionally for cholesterol with respect to the effects of enrichment. In cholesterol-depleted neurones, however, only incubation with cholesterol was able to restore GABA potency to normal. These results suggest a specific requirement for cholesterol at control levels to maintain optimal GABA potency, which may involve specific binding of cholesterol to the GABA(A) receptor. The reduction in GABA potency by enrichment with cholesterol or epicholesterol is more likely to be due to reduced plasma membrane fluidity.
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An imbalance in cholesterol homeostasis both at the presynaptic and postsynaptic side is likely to impact neurotransmission and induce the loss of synapses and dendritic spines.
“Thus, an imbalance in cholesterol homeostasis both at the presynaptic and postsynaptic side is likely to impact neurotransmission, and induce the loss of synapses and dendritic spines [11,12].”
From Loss of Mevalonate/Cholesterol Homeostasis in the Brain: A Focus on Autism Spectrum Disorder and Rett Syndrome (2019) · cites this paper as [11]
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References 24 · Cited by 153
- Authors
- Sooksawate, T., & Simmonds, M. A.
- Affiliations
- University of London (GB)
- Corresponding author
- Simmonds, M.A
- ORCID
- Sooksawate, T
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2001-01
- Volume
- 40
- Issue
- 2
- Pages
- 178-184
- ISSN
- 0028-3908 (ISSN-L)
- OpenAlex
- W1970363807
- Cited by
- 153
- References
- 24
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 4 · 2023: 6 · 2022: 7 · 2021: 6 · 2020: 7 · 2019: 14 · 2018: 8 · 2017: 6 · 2016: 12 · 2015: 6 · 2014: 7 · 2013: 4 · 2012: 2
- FWCI
- 3.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Chulalongkorn University
- Medical Research Council
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- membrane cholesterol, GABAA receptor, GABA sensitivity, hippocampal neurons, methyl-β-cyclodextrin, epicholesterol, bicuculline, picrotoxin, plasma membrane fluidity, receptor agonist potency, cholesterol binding
- MeSH terms
- Animals, Cell Membrane, Cells, Cultured, Cholesterol, gamma-Aminobutyric Acid, Hippocampus, Male, Neurons, Receptors, GABA-A, Stereoisomerism, Rats, Wistar, Patch-Clamp Techniques, Rats
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