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Functional specificity of liquid-liquid phase separation at the synapse

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  • Natalie J. Guzikowski

    (Vanderbilt University
    Vanderbilt University)

  • Ege T. Kavalali

    (Vanderbilt University
    Vanderbilt University)

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.

Suggested Citation

  • Natalie J. Guzikowski & Ege T. Kavalali, 2024. "Functional specificity of liquid-liquid phase separation at the synapse," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54423-7
    DOI: 10.1038/s41467-024-54423-7
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