Preprint
Placental Insulin-like Growth Factor 1 Deficiency Drives Autism-Relevant Behavioral Changes with Sex-Specific Vulnerabilities
bioRxiv
Cold Spring Harbor Laboratory
01/06/2026
DOI: 10.64898/2026.01.06.697024
PMID: 41542650
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.
Details
- Title: Subtitle
- Placental Insulin-like Growth Factor 1 Deficiency Drives Autism-Relevant Behavioral Changes with Sex-Specific Vulnerabilities
- Creators
- Annemarie J Carver - University of IowaFaith M Fairbairn - University of IowaRobert J Taylor Jr - University of Iowa, PsychiatryBenjamin W Q Hing - University of IowaAmrita Gajmer - University of IowaRegan T Fair - University of IowaHanna E Stevens - University of Iowa
- Resource Type
- Preprint
- Publication Details
- bioRxiv
- DOI
- 10.64898/2026.01.06.697024
- PMID
- 41542650
- NLM abbreviation
- bioRxiv
- ISSN
- 2692-8205
- eISSN
- 2692-8205
- Publisher
- Cold Spring Harbor Laboratory; United States
- Grant note
- T32 GM008629 / NIGMS NIH HHS T32 GM145441 / NIGMS NIH HHS R25 TR004393 / NCATS NIH HHS
- Language
- English
- Date posted
- 01/06/2026
- Academic Unit
- Molecular Physiology and Biophysics; Psychiatry; Iowa Neuroscience Institute
- Record Identifier
- 9985129654802771
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