GABA and astrocytic cholesterol determine the lipid environment of GABAAR in cultured cortical neurons
Abstract The γ-aminobutyric acid (GABA) type A receptor (GABAAR), a GABA activated pentameric chloride channel, mediates fast inhibitory neurotransmission in the brain. The lipid environment is critical for GABAAR function. How lipids regulate the channel in the cell membrane is not fully understood...
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| Format: | Article |
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Nature Portfolio
2025-04-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-08026-7 |
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| author | Zixuan Yuan Mahmud Arif Pavel Scott B. Hansen |
| author_facet | Zixuan Yuan Mahmud Arif Pavel Scott B. Hansen |
| author_sort | Zixuan Yuan |
| collection | DOAJ |
| description | Abstract The γ-aminobutyric acid (GABA) type A receptor (GABAAR), a GABA activated pentameric chloride channel, mediates fast inhibitory neurotransmission in the brain. The lipid environment is critical for GABAAR function. How lipids regulate the channel in the cell membrane is not fully understood. Here we employed super resolution imaging of lipids to demonstrate that the agonist GABA induces a rapid and reversible membrane translocation of GABAAR to phosphatidylinositol 4,5-bisphosphate (PIP2) clusters in mouse primary cortical neurons. This translocation relies on nanoscopic separation of PIP2 clusters and lipid rafts (cholesterol-dependent ganglioside clusters). In a resting state, the GABAAR associates with lipid rafts and this colocalization is enhanced by uptake of astrocytic secretions. These astrocytic secretions delay desensitization and enhance maximum current. In an Alzheimer’s Disease (AD) mouse model with high brain cholesterol, GABAAR shifts into lipid rafts. Our findings suggest cholesterol is a signaling molecule and astrocytes regulates GABAARs in neurons by secreting cholesterol. The findings have implications for treating mood disorders and AD associated with altered brain lipids. |
| format | Article |
| id | doaj-art-a404fbabf0ae4abe8092a2a2bd37eb1e |
| institution | DOAJ |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-a404fbabf0ae4abe8092a2a2bd37eb1e2025-08-20T03:15:10ZengNature PortfolioCommunications Biology2399-36422025-04-018111310.1038/s42003-025-08026-7GABA and astrocytic cholesterol determine the lipid environment of GABAAR in cultured cortical neuronsZixuan Yuan0Mahmud Arif Pavel1Scott B. Hansen2Department of Molecular Medicine, The Scripps Research InstituteDepartment of Molecular Medicine, The Scripps Research InstituteDepartment of Molecular Medicine, The Scripps Research InstituteAbstract The γ-aminobutyric acid (GABA) type A receptor (GABAAR), a GABA activated pentameric chloride channel, mediates fast inhibitory neurotransmission in the brain. The lipid environment is critical for GABAAR function. How lipids regulate the channel in the cell membrane is not fully understood. Here we employed super resolution imaging of lipids to demonstrate that the agonist GABA induces a rapid and reversible membrane translocation of GABAAR to phosphatidylinositol 4,5-bisphosphate (PIP2) clusters in mouse primary cortical neurons. This translocation relies on nanoscopic separation of PIP2 clusters and lipid rafts (cholesterol-dependent ganglioside clusters). In a resting state, the GABAAR associates with lipid rafts and this colocalization is enhanced by uptake of astrocytic secretions. These astrocytic secretions delay desensitization and enhance maximum current. In an Alzheimer’s Disease (AD) mouse model with high brain cholesterol, GABAAR shifts into lipid rafts. Our findings suggest cholesterol is a signaling molecule and astrocytes regulates GABAARs in neurons by secreting cholesterol. The findings have implications for treating mood disorders and AD associated with altered brain lipids.https://doi.org/10.1038/s42003-025-08026-7 |
| spellingShingle | Zixuan Yuan Mahmud Arif Pavel Scott B. Hansen GABA and astrocytic cholesterol determine the lipid environment of GABAAR in cultured cortical neurons Communications Biology |
| title | GABA and astrocytic cholesterol determine the lipid environment of GABAAR in cultured cortical neurons |
| title_full | GABA and astrocytic cholesterol determine the lipid environment of GABAAR in cultured cortical neurons |
| title_fullStr | GABA and astrocytic cholesterol determine the lipid environment of GABAAR in cultured cortical neurons |
| title_full_unstemmed | GABA and astrocytic cholesterol determine the lipid environment of GABAAR in cultured cortical neurons |
| title_short | GABA and astrocytic cholesterol determine the lipid environment of GABAAR in cultured cortical neurons |
| title_sort | gaba and astrocytic cholesterol determine the lipid environment of gabaar in cultured cortical neurons |
| url | https://doi.org/10.1038/s42003-025-08026-7 |
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