Essential lipids enrich membrane-associated condensates to rescue synaptic morpho-functional deficits in a mouse...

Synaptic proteins form intracellular condensates with their scaffolds, but it is unknown whether and how essential lipids transform dynamic cytosolic condensates into stable, functional macromolecular assemblies at the membrane. We show that docosahexaenoic acid (DHA), independent of canonical fatty acid receptor 4 signaling, facilitates the re-localization of cytosolic "full-droplet" condensates composed of the key synaptic elements PSD95 and Kv1.2 to the plasma membrane as "half-droplets." To exploit the therapeutic potential of DHA in vivo, we briefly place juvenile wild-type and Fmr1 KO mice, modeling human fragile X syndrome (FXS), under DHA-enriched or -depleted diets. DHA reverses the inhibitory overtone by promoting the re-localization of presynaptic PSD95-Kv1.2 condensates to interneuron terminal membranes and corrects morpho-functional synaptic defects and stereotypic behaviors. These findings reveal an unexpected role of essential lipids in translocating dynamic condensates into stable synaptic condensates, providing long-lasting benefits for rectifying excitation-inhibition imbalance in FXS and potentially other neurodevelopmental disorders.