Functional specificity of liquid-liquid phase separation at the synapse
Abstract The mechanisms that enable synapses to achieve temporally and spatially precise signaling at nano-scale while being fluid with the cytosol are poorly understood. Liquid-liquid phase separation (LLPS) is emerging as a key principle governing subcellular organization; however, the impact of s...
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54423-7 |
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| author | Natalie J. Guzikowski Ege T. Kavalali |
| author_facet | Natalie J. Guzikowski Ege T. Kavalali |
| author_sort | Natalie J. Guzikowski |
| collection | DOAJ |
| description | Abstract The mechanisms that enable synapses to achieve temporally and spatially precise signaling at nano-scale while being fluid with the cytosol are poorly understood. Liquid-liquid phase separation (LLPS) is emerging as a key principle governing subcellular organization; however, the impact of synaptic LLPS on neurotransmission is unclear. Here, using rat primary hippocampal cultures, we show that robust disruption of neuronal LLPS with aliphatic alcohols severely dysregulates action potential-dependent neurotransmission, while spontaneous neurotransmission persists. Synaptic LLPS maintains synaptic vesicle pool clustering and recycling as well as the precise organization of active zone RIM1/2 and Munc13 nanoclusters, thus supporting fast evoked Ca2+-dependent release. These results indicate although LLPS is necessary within the nanodomain of the synapse, the disruption of this nano-organization largely spares spontaneous neurotransmission. Therefore, properties of in vitro micron sized liquid condensates translate to the nano-structure of the synapse in a functionally specific manner regulating action potential-evoked release. |
| format | Article |
| id | doaj-art-71ad134f8f7b44799e024458d4c6de47 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-71ad134f8f7b44799e024458d4c6de472025-08-20T02:33:05ZengNature PortfolioNature Communications2041-17232024-11-0115111410.1038/s41467-024-54423-7Functional specificity of liquid-liquid phase separation at the synapseNatalie J. Guzikowski0Ege T. Kavalali1Department of Pharmacology, Vanderbilt UniversityDepartment of Pharmacology, Vanderbilt UniversityAbstract The mechanisms that enable synapses to achieve temporally and spatially precise signaling at nano-scale while being fluid with the cytosol are poorly understood. Liquid-liquid phase separation (LLPS) is emerging as a key principle governing subcellular organization; however, the impact of synaptic LLPS on neurotransmission is unclear. Here, using rat primary hippocampal cultures, we show that robust disruption of neuronal LLPS with aliphatic alcohols severely dysregulates action potential-dependent neurotransmission, while spontaneous neurotransmission persists. Synaptic LLPS maintains synaptic vesicle pool clustering and recycling as well as the precise organization of active zone RIM1/2 and Munc13 nanoclusters, thus supporting fast evoked Ca2+-dependent release. These results indicate although LLPS is necessary within the nanodomain of the synapse, the disruption of this nano-organization largely spares spontaneous neurotransmission. Therefore, properties of in vitro micron sized liquid condensates translate to the nano-structure of the synapse in a functionally specific manner regulating action potential-evoked release.https://doi.org/10.1038/s41467-024-54423-7 |
| spellingShingle | Natalie J. Guzikowski Ege T. Kavalali Functional specificity of liquid-liquid phase separation at the synapse Nature Communications |
| title | Functional specificity of liquid-liquid phase separation at the synapse |
| title_full | Functional specificity of liquid-liquid phase separation at the synapse |
| title_fullStr | Functional specificity of liquid-liquid phase separation at the synapse |
| title_full_unstemmed | Functional specificity of liquid-liquid phase separation at the synapse |
| title_short | Functional specificity of liquid-liquid phase separation at the synapse |
| title_sort | functional specificity of liquid liquid phase separation at the synapse |
| url | https://doi.org/10.1038/s41467-024-54423-7 |
| work_keys_str_mv | AT nataliejguzikowski functionalspecificityofliquidliquidphaseseparationatthesynapse AT egetkavalali functionalspecificityofliquidliquidphaseseparationatthesynapse |