The functional neuronal lipotype is specified by activity and PS synthesis using dietary and lysosomal inputs

Neurons possess specialized membranes essential for lifelong circuit function, yet the precise mechanisms behind the enrichment of specific lipids remains unclear. Researchers have now identified a conserved characteristic of mature neurons: phosphatidylserines containing omega-3 fatty acids (n-3 PS), which accumulate dynamically during synaptogenesis across various species, from Drosophila to humans.

This unique lipotype relies on dietary n-3 fatty acids, lysosomal catabolism facilitated by Saposin, phospholipase PLA2G15, and the lysophospholipid transporter spin/SPNS1. When neuronal PS biosynthesis was reduced by targeting the PS synthase (Pss), detrimental effects on lipid composition, synapses, and behavior were observed, further exacerbated by impaired glycerophospholipid catabolism.

Manipulations related to diet, lysosomal activity, and lipoproteins also altered n-3 levels, but silencing developmental, activity-driven neurons selectively lowered n-3 PS. Intriguingly, pathogenic Pss variants, lacking feedback inhibition, demonstrated comparable reductions in n-3 PS and impaired circuit function. Moreover, the levels of n-3 PS decline during neurodegeneration, and this critical lipid characteristic is absent in iPSC-derived neurons, suggesting potential disparities in the recapitulation of lipotype and physiology in vitro.