Dysregulation of synaptogenesis in fetal growth restriction

DOI

https://dx.doi.org/10.18565/aig.2026.132

Kan N.E., Gusar V.A., Zolotareva A.P., Tyutyunnik V.L., Leonova A.A., Chagovets V.V., Alieva L.E.
1) Academician V.I. Kulakov National Medical Research Centre of Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, Moscow, Russia; 2) Primorsky Regional Perinatal Center, Vladivostok, Russia

Objective. To evaluate the expression of synaptic proteins within fetal neuronal vesicles (FNVs) in early- and late-onset fetal growth restriction (FGR) and to determine their associations with neonatal complications.
Materials and methods. One hundred and twenty pregnant women were enrolled in the study. The study group comprised 60 patients with a postnatally confirmed diagnosis of FGR: 30 with early-onset FGR and 30 with late-onset FGR. The control group comprised 60 pregnant women matched by gestational age at delivery. The expression of the synaptic proteins synapsin 1 (SYN1), synaptotagmin 1 (SYT1), synaptophysin (SYP), synaptopodin (SYNPO), and postsynaptic density protein 95 (PSD95) within FNVs was assessed using western blotting.
Results. Early-onset FGR was associated with statistically significant reductions in SYN1 and SYT1 expression and an elevation in SYP expression. Late-onset FGR was associated with reduced SYN1 expression and elevated SYNPO and SYP levels. The most pronounced difference in the proteomic profiles between early- and late-onset FGR was SYP, with its expression significantly higher in late-onset FGR. Analysis of neonatal outcomes revealed that in early-onset FGR, altered synaptic protein expression was associated with central nervous system (CNS) depression syndrome and intraventricular hemorrhage (IVH), whereas in late-onset FGR, it was associated exclusively with IVH. Correlations were identified between synaptic protein expression levels and Doppler indices of uteroplacental and fetoplacental blood flows.
Conclusion. The assessment of synaptic protein expression within FNVs represents a promising approach for the non-invasive prenatal diagnosis of synaptogenesis impairment in FGR. The observed alterations may reflect the disruption and/or dysregulation of synaptic contact formation in the fetus and may serve as potential biomarkers for adverse neurological outcomes.

Authors’ contributions. Kan N.E., Gusar V.A., Zolotareva A.P., Tyutyunnik V.L., Leonova A.A., Chagovets V.V., Alieva L.E. – concept and design of the study, data acquisition, literature review, processing and analysis of material on the topic, drafting of the manuscript, editing of the manuscript.
Conflicts of interest. The authors have no conflicts of interest to declare.
Funding. The study was conducted within the framework of the independent research topic «Epigenetic criteria for diagnosing fetal growth restriction from the perspective of neurogenesis dysfunction» Research Work No. 19-I23 (dated 08.12.22) (Registration number in the Unified State Information System for Accounting of Research, Development, and Technological Works (state registration) – 123060500032-8).
Ethical Approval. The study was reviewed and approved by the Research Ethics Committee of the V.I. Kulakov NMRC for OG&P (Protocol No. 10 dated October 20, 2022).
Use of generative artificial intelligence. None.
Patient Consent for Publication. All patients provided informed consent for the publication of their data.
Authors' Data Sharing Statement. The data supporting the findings of this study are available upon request from the corresponding author after approval from the principal investigator.
For citation: Kan N.E., Gusar V.A., Zolotareva A.P., Tyutyunnik V.L., Leonova A.A.,
Chagovets V.V., Alieva L.E. Dysregulation of synaptogenesis in fetal growth restriction.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2026; (5): 78-88 (in Russian)
https://dx.doi.org/10.18565/aig.2026.132

fetal growth restriction

fetal neuronal vesicles

extracellular vesicles

synaptogenesis

synapsin 1

synaptophysin

synaptotagmin 1

synaptopodin

postsynaptic density protein 95

SYN1

SYT1

SYP

SYNPO

PSD95

perinatal brain injury

Full text (in Russian)

Lei T.Y., Li D.Z. Perinatal outcome of late-onset fetal growth restriction: etiology matters. Ultrasound Obstet. Gynecol. 2022; 60(5): 707-8. https://dx.doi.org/10.1002/uog.26087
van de Meent M., Bel E.W., Ganzevoort W., Gordijn S.J., Groenendaal F., Kooi E.M.W. et al.; on behalf of the OPtimal TIming of antenatal COrticosteroids in pregnancies complicated by early‐onset fetal growth REstriction (OPTICORE) study group. Perinatal risk assessment in pregnancies complicated by early-onset fetal growth restriction: development and internal validation of a prediction model for composite adverse perinatal outcome. Ultrasound Obstet. Gynecol. 2025; 66(2): 175-85. https://dx.doi.org/10.1002/uog.29123
Larsen M.L., Krebs L., Hoei-Hansen C.E., Kumar S. Assessment of fetal growth trajectory identifies infants at high risk of perinatal mortality. Ultrasound Obstet. Gynecol. 2024; 63(6): 764-71. https://dx.doi.org/10.1002/uog.27589
Министерство здравоохранения Российской Федерации. Клинические рекомендации. Недостаточный рост плода, требующий предоставления медицинской помощи матери (задержка роста плода). М.; 2025. 69 с. [Ministry of Health of the Russian Federation. Clinical guidelives. Insufficient growth of the fetus, requiring the provision of medical care to the mother (fetal growth retardation). Moscow; 2025. 69 p. (in Russian)].
Adam-Raileanu A., Miron I., Lupu A., Bozomitu L., Sasaran M.O., Russu R. et al. Fetal growth restriction and its metabolism-related long-term outcomes—underlying mechanisms and clinical implications. Nutrients. 2025; 17(3): 555. https://dx.doi.org/10.3390/nu17030555
Ni W., Gao X., Su X., Cai J., Zhang S., Zheng L. et al. Birth spacing and risk of adverse pregnancy and birth outcomes: A systematic review and dose–response meta‐analysis. Acta Obstet. Gynecol. Scand. 2023; 102(12): 1618-33. https://dx.doi.org/10.1111/aogs.14648
Sacchi C., O'Muircheartaigh J., Batalle D., Counsell S.J., Simonelli A., Cesano M. et al. Neurodevelopmental outcomes following intrauterine growth restriction and very preterm birth. J. Pediatr. 2021; 238: 135-144.e10. https://dx.doi.org/10.1016/j.jpeds.2021.07.002
Bahia M.L.R., Velarde G.C., Silva F.C.D., Araujo Júnior E., Sá R.A.M. Adverse perinatal outcomes in fetuses with severe late-onset fetal growth restriction. J. Matern. Fetal Neonatal Med. 2022; 35(25): 8666-72. https://dx.doi.org/10.1080/14767058.2021.1995858
Юсенко С.Р., Траль Т.Г., Толибова Г.Х., Коган И.Ю. Морфологические особенности плацент при хронической плацентарной недостаточности и задержке роста плода. Вопросы гинекологии, акушерства и перинатологии. 2022; 21(3): 95-101. [Yusenko S.R., Tral T.G., Tolibova G.Kh., Kogan I.Yu. Placental morphology in chronic placental insufficiency and fetal growth restriction. Gynecology, Obstetrics and Perinatology. 2022; 21(3): 95-101. (in Russian)]. https://dx.doi.org/10.20953/1726-1678-2022-3-95-101
Melamed N., Baschat A., Yinon Y., Athanasiadis A., Mecacci F., Figueras F. et al. FIGO (International Federation of Gynecology and Obstetrics) initiative on fetal growth: best practice advice for screening, diagnosis, and management of fetal growth restriction. Int. J. Gynecol. Obstet. 2021; 152(S1): 3-57. https://dx.doi.org/10.1002/ijgo.13522
American College of Obstetricians and Gynecologists' Committee on Practice Bulletins—Obstetrics and the Society for Maternal-Fetal Medicine. ACOG Practice Bulletin No. 204: Fetal Growth Restriction. Obstet. Gynecol. 2019; 133(2): e97-e109. https://dx.doi.org/10.1097/AOG.0000000000003070
Afzal A., Khan M., Gul Z., Asif R., Shahzaman S., Parveen A. et al. Extracellular vesicles: the next frontier in pregnancy research. Reprod. Sci. 2023; 31(5): 1204-14. https://dx.doi.org/10.1007/s43032-023-01434-2
Goetzl L., Darbinian N., Goetzl E.J. Novel window on early human neurodevelopment via fetal exosomes in maternal blood. Ann. Clin. Transl. Neurol. 2016; 3(5): 381-5. https://dx.doi.org/10.1002/acn3.296
Salomon C., Nuzhat Z., Dixon C.L., Menon R. Placental exosomes during gestation: liquid biopsies carrying signals for the regulation of human parturition. Curr. Pharm. Des. 2018; 24(9): 974-82. https://dx.doi.org/10.2174/1381612824666180125104428
Miranda J., Paules C., Nair S., Lai A., Palma C., Scholz-Romero K. et al. Placental exosomes profile in maternal and fetal circulation in intrauterine growth restriction – Liquid biopsies to monitoring fetal growth. Placenta. 2018; 64: 34-43. https://dx.doi.org/10.1016/j.placenta.2018.02.006
Gusar V., Kan N., Leonova A., Chagovets V., Tyutyunnik V., Khachatryan Z. et al. Non-invasive assessment of neurogenesis dysfunction in fetuses with early-onset growth restriction using fetal neuronal exosomes isolating from maternal blood: A pilot study. Int. J. Mol. Sci. 2025; 26(4): 1497. https://dx.doi.org/110.3390/ijms26041497
Кан Н.Е., Леонова А.А., Гусар В.А., Чаговец В.В., Тютюнник В.Л., Волочаева М.В., Солдатова Е.Е., Рыжова К.О., Серебрякова А.П. Критерии оценки дисфункции нейрогенеза плода с ранней задержкой роста с использованием внеклеточных везикул. Акушерство и гинекология. 2025; 3: 56-64. [Kan N.E., Leonova A.A., Gusar V.A., Chagovets V.V., Tyutyunnik V.L., Volochaeva M.V., Soldatova E.E., Ryzhova K.O., Serebriakova A.P. Criteria for assessing fetal neurogenesis dysfunction in early-onset growth restriction using extracellular vesicles. Obstetrics and Gynecology. 2025; (3): 56-64 (in Russian)]. https://dx.doi.org/10.18565/aig.2025.30
Gusar V., Kan N., Leonova A., Chagovets V., Tyutyunnik V., Zolotareva A. et al. Fetal neuronal vesicles in the assessment of perinatal brain dysfunction and late-onset growth restriction: A pilot study. Int. J. Mol. Sci. 2026; 27(2): 679. https://dx.doi.org/10.3390/ijms27020679
Sarnat H.B. Sequences of synaptogenesis in the human fetal and neonatal brain by synaptophysin immunocytochemistry. Front. Cell. Neurosci. 2023; 17: 1105183. https://dx.doi.org/10.3389/fncel.2023.1105183
Qi C., Luo L.D., Feng I., Ma S. Molecular mechanisms of synaptogenesis. Front. Synaptic Neurosci. 2022; 14: 939409. https://dx.doi.org/10.3389/fnsyn.2022.939793.
Fornasiero E.F., Bonanomi D., Benfenati F., Valtorta F. The role of synapsins in neuronal development. Cell. Mol. Life Sci. 2010; 67(9):1383-96. https://dx.doi.org/10.1007/s00018-009-0227-8
Cesca F., Baldelli P., Valtorta F., Benfenati F. The synapsins: Key actors of synapse function and plasticity. Prog. Neurobiol. 2010; 91(4): 313-48. https://dx.doi.org/10.1016/j.pneurobio.2010.04.006
Jovanovic J.N., Czernik A.J., Fienberg A.A., Greengard P., Sihra T.S. Synapsins as mediators of BDNF-enhanced neurotransmitter release. Nat. Neurosci. 2000; 3(4): 323-9. https://dx.doi.org/10.1038/73888
Corradi A., Zanardi A., Giacomini C., Onofri F., Valtorta F., Zoli M. et al. Synapsin-I- and synapsin-II-null mice display an increased age-dependent cognitive impairment. J. Cell Sci. 2008; 121 (18): 3042-3051. https://dx.doi.org/10.1242/jcs.030692
Tang L.T., Craig T.J., Henley J.M. SUMOylation of synapsin Ia maintains synaptic vesicle availability and is reduced in an autism mutation. Nat. Commun. 2015; 6(1): 7728. https://dx.doi.org/10.1038/ncomms8728
Cousin M.A. Synaptophysin‐dependent synaptobrevin‐2 trafficking at the presynapse‐Mechanism and function. J. Neurochem. 2021; 159(1): 78-89. https://dx.doi.org/10.1111/jnc.15499
White D.N., Stowell M.H.B. Room for two: the synaptophysin/synaptobrevin Complex. Front. Synaptic Neurosci. 2021; 13: 740371. https://dx.doi.org/10.3389/fnsyn.2021.740371

Received 22.04.2026

Accepted 08.05.2026

Natalia E. Kan, Professor, Dr. Med. Sci., Honored Scientist of the Russian Federation, Deputy Director of Science, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparina str., 4, kan-med@mail.ru,
Researcher ID: B-2370-2015, SPIN-code: 5378-8437, Authors ID: 624900, Scopus Author ID: 57008835600, https://orcid.org/0000-0001-5087-5946
Vladislava A. Gusar, PhD, Senior Researcher at the Laboratory of Transcriptomic, Department of Systems Biology in Reproduction, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparina str., 4, v_gusar@oparina4.ru,
https://orcid.org/0000-0003-3990-6224
Anna P. Zolotareva, Applicant, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia,
117997, Russia, Moscow, Ac. Oparina str., 4; obstetrician-gynecologist at the day hospital department for examination of pregnant women, Primorsky Regional Perinatal Center, 690042, Russia, Vladivostok, Mozhayskaya str., 1B, serebriakovanna@gmail.com, https://orcid.org/0000-0001-7014-2627
Victor L. Tyutyunnik, Professor, Dr. Med. Sci., Honored Doctor of the Russian Federation, Leading Researcher at the Center for Scientific and Clinical Research, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparina str. 4, tioutiounnik@mail.ru, Researcher ID: B-2364-2015, SPIN-code: 1963-1359, Authors ID: 213217, Scopus Author ID: 56190621500, https://orcid.org/0000-0002-5830-5099
Anastasia A. Leonova, PhD, obstetrician-gynecologist at the Obstetric Department, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparina str. 4, +7(937)453-54-27, nastena27-03@mail.ru, https://orcid.org/0000-0001-6707-3464
Vitaliy V. Chagovets, PhD, Senior Researcher at the Laboratory of Transcriptomic, Department of Systems Biology in Reproduction, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparina str., 4, vvchagovets@gmail.com,
https://orcid.org/0000-0002-5120-376X
Leyla E. Alieva, PhD student, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia,
117997, Russia, Moscow, Ac. Oparina str., 4, leylaalieva00@mail.ru, https://orcid.org/0009-0008-3417-6721
Corresponding author: Anastasia A. Leonova, nastena27-03@mail.ru

Dysregulation of synaptogenesis in fetal growth restriction

Kan N.E., Gusar V.A., Zolotareva A.P., Tyutyunnik V.L., Leonova A.A., Chagovets V.V., Alieva L.E.

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