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Converging evidence has positioned the serotonergic system as a key organizer of the brain during development and across the lifespan; however, the principles determining when serotonin acts permissively or instructively remains unresolved. In this Review, we critically examine interventional studies across sensitive developmental and adult windows to assess whether serotonergic signaling acts in a sex-dependent manner to shape circuit architecture and bias vulnerability to neurodevelopmental and psychiatric disorders. We argue that the consequences of serotonergic perturbation depend on developmental timing, biological sex, hormonal context, and circuit identity, rather than solely on serotonin levels. Finally, we discuss how staged interactions among serotonergic signaling, endocrine state, and circuit phenotypes\u2014potentially modulated by RNA-centered regulatory processes\u2014may offer a mechanistically plausible framework through which transient environmental challenges acquire lasting effects on neurodevelopmental and affective vulnerability.<\/jats:p>","DOI":"10.3389\/fphar.2026.1800447","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T05:37:50Z","timestamp":1776922670000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Sex-dependent serotonergic signaling across development: molecular mechanisms shaping vulnerability to neurodevelopmental and mental disorders"],"prefix":"10.3389","volume":"17","author":[{"given":"Nicol\u00e1s","family":"Palacios-Avenda\u00f1o","sequence":"first","affiliation":[{"name":"Laboratory of Neuroplasticity and Neurogenetics, Department of Biochemistry and Molecular Biology, Faculty of Chemical and Pharmaceutical Sciences, Universidad de Chile","place":["Santiago, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulina S.","family":"Rojas","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, School of Pharmacy, Universidad Andres Bello","place":["Santiago, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mat\u00edas","family":"Alarc\u00f3n-Mardones","sequence":"additional","affiliation":[{"name":"Laboratory of Neuroplasticity and Neurogenetics, Department of Biochemistry and Molecular Biology, Faculty of Chemical and Pharmaceutical Sciences, Universidad de Chile","place":["Santiago, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny L.","family":"Fiedler","sequence":"additional","affiliation":[{"name":"Laboratory of Neuroplasticity and Neurogenetics, Department of Biochemistry and Molecular Biology, Faculty of Chemical and Pharmaceutical Sciences, Universidad de Chile","place":["Santiago, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"105517","DOI":"10.1016\/j.nsa.2025.105517","article-title":"Sex hormones and serotonin 4 receptor brain binding in men with and without major depressive disorder","volume":"4","author":"Aarestrup","year":"2025","journal-title":"Neurosci. 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