Maternal serotonin transporter genotype influences offspring’s anxiety-like behavior through prenatal and early postnatal routes

Maternal serotonin transporter (5-HTT) genotype has been linked to offspring’s risk for neuropsychiatric disorders, yet the contribution of prenatal versus early postnatal routes remains unresolved. We combined a 5-HTT −/− rat model with a fostering procedure to disentangle these effects. 5-HTT +/− offspring genotype was kept constant by crossing 5-HTT −/− or 5-HTT +/+ dams with males of opposite genotypes. Prenatally, compared with 5-HTT +/+ dams, 5-HTT −/− dams produced smaller embryos with impaired serotonergic maturation. Their placentas exhibited alterations in serotonergic-related signaling. Postnatally, 5-HTT −/− dams exhibited reduced licking and grooming. Adult offspring from 5-HTT −/− dams showed lower anxiety-like behavior alongside altered corticosterone recovery following stress and elevated infralimbic Gad67 expression relative to offspring from 5-HTT +/+ dams. To dissociate prenatal from postnatal influences, offspring were cross-fostered with genotype-mismatched dams. Under cross-fostering, offspring from 5-HTT −/− dams exhibited a higher serotonin/tryptophan ratio and reduced Bdnf isoform VI expression in the medial prefrontal cortex compared to offspring from 5-HTT +/+ dams. Independent of biological dam genotype, cross-fostering reduced body weight, increased anxiety-like behavior, and downregulated HPA-axis- and GABA/glutamatergic-related signaling. Here, we demonstrate that maternal 5-HTT genotype shapes offspring’s anxiety-like behavior through combined prenatal and early postnatal effects, highlighting the intertwined roles of maternal genetics and environment in neuropsychiatric disorders' pathophysiology.

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Publication Details

Journal
Scientific Reports
Published
2026-09-01
DOI
https://doi.org/10.1038/s41598-026-68310-2
Primary Topic
Maternal Mental Health During Pregnancy and Postpartum
Type
article
Field-Weighted Citation Impact
0.00

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article

Maternal serotonin transporter genotype influences offspring’s anxiety-like behavior through prenatal and early postnatal routes

Qiuyuan Fang, Weizhuo Li, Rick Greupink, Sylvia Docq et al.
Scientific Reports
Maternal Mental Health During Pregnancy and Postpartum
article

Maternal serotonin transporter genotype influences offspring’s anxiety-like behavior through prenatal and early postnatal routes

Qiuyuan Fang, Weizhuo Li, Rick Greupink, Sylvia Docq, Chunqing Liu, Marloes J. A. G. Henckens, Anthonieke Middelman, Celine A.J. Smits, Tianhua Wang, Paola Brivio, Michel M. M. Verheij, Markus Wöhr, Petra H.H. van den Broek, Xianzong Meng, Lisa C.M.W. Heltzel, Francesca Calabrese, Marcia Spoelder, Brianna N. Natale, Marta C. F. Samina, Roël Vrooman, D Peeters, Judith R. Homberg, S.I. Hanswijk, R.C.R. Castro, Petronella D. H. van den Burg, Ling Shan, Jan K. Buitelaar, Sharon M. Kolk
article en

Abstract

Maternal serotonin transporter (5-HTT) genotype has been linked to offspring’s risk for neuropsychiatric disorders, yet the contribution of prenatal versus early postnatal routes remains unresolved. We combined a 5-HTT −/− rat model with a fostering procedure to disentangle these effects. 5-HTT +/− offspring genotype was kept constant by crossing 5-HTT −/− or 5-HTT +/+ dams with males of opposite genotypes. Prenatally, compared with 5-HTT +/+ dams, 5-HTT −/− dams produced smaller embryos with impaired serotonergic maturation. Their placentas exhibited alterations in serotonergic-related signaling. Postnatally, 5-HTT −/− dams exhibited reduced licking and grooming. Adult offspring from 5-HTT −/− dams showed lower anxiety-like behavior alongside altered corticosterone recovery following stress and elevated infralimbic Gad67 expression relative to offspring from 5-HTT +/+ dams. To dissociate prenatal from postnatal influences, offspring were cross-fostered with genotype-mismatched dams. Under cross-fostering, offspring from 5-HTT −/− dams exhibited a higher serotonin/tryptophan ratio and reduced Bdnf isoform VI expression in the medial prefrontal cortex compared to offspring from 5-HTT +/+ dams. Independent of biological dam genotype, cross-fostering reduced body weight, increased anxiety-like behavior, and downregulated HPA-axis- and GABA/glutamatergic-related signaling. Here, we demonstrate that maternal 5-HTT genotype shapes offspring’s anxiety-like behavior through combined prenatal and early postnatal effects, highlighting the intertwined roles of maternal genetics and environment in neuropsychiatric disorders' pathophysiology.

Scientific Reports
Netherlands Institute for Neuroscience (NL), Royal Netherlands Academy of Arts and Sciences (NL), Radboud University Nijmegen (NL), Philipps University of Marburg (DE), University of Milan (IT), Dalian Medical University (CN), Radboud University Medical Center (NL), Radboud Institute for Molecular Life Sciences (NL), Dutch Expert Centre for Screening (NL), Karakter (NL), VIB-KU Leuven Center for Brain & Disease Research (BE), KU Leuven (BE)
Koninklijke Nederlandse Akademie van Wetenschappen, Radboud Universiteit, Fonds Wetenschappelijk Onderzoek, Radboud Universitair Medisch Centrum, Vlaamse regering, Horizon 2020 Framework Programme
Openalex Percentile: Top 13%
Maternal Mental Health During Pregnancy and Postpartum
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