{
  "abstract": "Neurons maintain specialized membranes necessary for lifelong circuit function. While neuronal membranes thus contain unique lipidomes, how and why specific lipids become synaptically enriched remains mysterious. Here, we identify a conserved hallmark of mature neurons, phosphatidylserines containing omega-3 fatty acids (n-3 PS), which dynamically accumulate during synaptogenesis from Drosophila to humans. This neuronal lipotype depends on dietary n-3 and lysosomal catabolism mediated by Saposin, the phospholipase PLA2G15, and the lysophospholipid transporter spin/SPNS1. Reducing neuronal PS biosynthesis by targeting the PS synthase (Pss) caused lipidomic, synaptic, and behavioral deficits exacerbated by impaired glycerophospholipid catabolism. While dietary, lysosomal, and lipoprotein manipulations broadly altered n-3 levels, silencing developmental activity-templating neurons selectively reduced n-3 PS. Remarkably, pathogenic Pss variants lacking feedback inhibition similarly reduced n-3 PS and impaired circuit function. As n-3 PS is reduced during neurodegeneration but absent from iPSC-derived neurons, important relationships between lipotype and physiology may not be recapitulated in vitro.",
  "abstract_shown": true,
  "affiliations": [
    "UCSF"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 15,
  "authors": [
    {
      "name": "R. J. Lee"
    },
    {
      "name": "I. M. Rivas-Serna"
    },
    {
      "name": "E. K. Theisen"
    },
    {
      "name": "A. Bibo"
    },
    {
      "name": "E. B. Hardy"
    },
    {
      "name": "W. Cheng"
    },
    {
      "name": "Z. Zhou"
    },
    {
      "name": "J. S. Chavez-Rios"
    },
    {
      "name": "J. C. Forward"
    },
    {
      "name": "T. T. Pham"
    },
    {
      "name": "C. I. Thomas"
    },
    {
      "name": "A. Darehshouri"
    },
    {
      "name": "V. Mazurak"
    },
    {
      "name": "M. T. Clandinin"
    },
    {
      "affs": [
        0
      ],
      "name": "J. Vaughen"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4ntw6db4x4949.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.26.754678",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.26.754678v1.full",
  "id": "4ntw6db4x4949",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.26.754678v1",
  "language": null,
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "neuroscience"
    ],
    [
      "openalex",
      "1303|Lipid metabolism and biosynthesis"
    ]
  ],
  "openalex": "W7215089891",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.26.754678v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-26",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/4ntw6db4x4949.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:25:41Z",
      "native_id": "10.64898/2026.09.26.754678",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.26.754678v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:neuroscience",
      "subfield": "neuroscience"
    }
  ],
  "title": "The functional neuronal lipotype is specified by activity and PS synthesis using dietary and lysosomal inputs",
  "title_text": "The functional neuronal lipotype is specified by activity and PS synthesis using dietary and lysosomal inputs",
  "type": "preprint",
  "updated_at": "2026-10-30T12:25:41Z",
  "url": "https://research.draconitic.com/paper/4ntw6db4x4949",
  "venue": "bioRxiv",
  "versions": []
}