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Placental Insulin-like Growth Factor 1 Deficiency Drives Autism-Relevant Behavioral Changes with Sex-Specific Vulnerabilities
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Placental Insulin-like Growth Factor 1 Deficiency Drives Autism-Relevant Behavioral Changes with Sex-Specific Vulnerabilities

Annemarie J Carver, Faith M Fairbairn, Robert J Taylor Jr, Benjamin W Q Hing, Amrita Gajmer, Regan T Fair and Hanna E Stevens
bioRxiv
Cold Spring Harbor Laboratory
01/06/2026
DOI: 10.64898/2026.01.06.697024
PMCID: PMC12803038
PMID: 41542650
url
https://doi.org/10.64898/2026.01.06.697024View
Preprint (Author's original) This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

Background Preterm birth and other perinatal adversities lead to the loss of placental support including critical hormones, such as insulin-like growth factor 1 (IGF1), required for neurodevelopment. Decreased IGF1 and preterm birth are associated with neurodevelopmental disorder risk, including autism spectrum disorder. Whether placental Igf1 insufficiency drives neurodevelopmental risks is not understood. Methods To understand these mechanisms, placental-targeted CRISPR manipulation in mice was employed to create placental Igf1 insufficiency. Subsequently, embryonic forebrain development was assessed sex-specifically to identify structural and transcriptomic changes. Postnatal offspring were used to determine neurobehavioral trajectories relevant to neurodevelopmental disorders as assessed through learning, motor, and affective behavioral tasks and neurostereology. Results Placental Igf1 insufficiency reduced embryonic forebrain growth, including decreased cell population across males and females. Embryonic forebrain transcriptomics revealed sex-specific alterations. Autism relevant developmental pathways were downregulated in male forebrain, driven by genes including Reln and Lama1. Altered genes in female forebrain were enriched for autism-risk genes including Grin2b and Dync1h1. Following these transcriptomic differences, postnatal neurobehavioral trajectories were sex specific. Male offspring uniquely showed reduced motor learning, increased stereotyped behaviors, altered reversal learning, and reduced forebrain neuronal number. Female offspring displayed opposite behavioral changes as males and few changes in forebrain structure. Conclusions The provision of Igf1 specifically from placenta is critical for offspring forebrain development. This temporary early deficit has persistent sex-specific neurobehavioral effects. These outcomes have relevance for autism risk and highlight mechanisms that could facilitate intervention development for adverse outcomes after early loss of placental hormone support in perinatal adversity.
 Placenta Insulin-like Growth Factor 1 Neurodevelopment Autism Spectrum Disorder Preterm Birth Neuroplacentology

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