vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/vjgb-24-46vavilov-4183Research ArticleГЕНЕТИКА ЖИВОТНЫХANIMAL GENETICSПаттерны экспрессии рецепторов дофамина и основных элементов нейротрофических (BDNF, CDNF) систем в критические периоды онтогенеза в структурах мозга мышей с аутизм-подобным поведением (BTBR) или его отсутствием (С57BL/6J)Dopamine receptors and key elements of the neurotrophins (BDNF, CDNF) expression patterns during critical periods of ontogenesis in the brain structures of mice with autism-like behavior (BTBR) or its absence (С57BL/6J)https://orcid.org/0000-0002-8187-3043ПравиковаП. Д.PravikovaP. D.

Новосибирск

Novosibirsk 

PollyPravi@yandex.ruАрссанМ. А.ArssanM. A.

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Novosibirsk 

ЗаливинаЕ. А.ZalivinaE. A.

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Novosibirsk 

https://orcid.org/0000-0002-0542-4481КондауроваЕ. М.KondaurovaE. M.

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Novosibirsk 

https://orcid.org/0000-0001-9102-1525КуликоваЕ. А.KulikovaE. A.

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Novosibirsk 

БелокопытоваИ. И.BelokopytovaI. I.

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Novosibirsk 

https://orcid.org/0000-0001-7196-4729НауменкоВ. С.NaumenkoV. S.

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Novosibirsk

Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наукРоссияInstitute of Cytology and Genetics of the Siberian Branch of the Russian Academy of SciencesRussian Federation202411072024284407415Copyright © Правикова П.Д., Арссан М.А., Заливина Е.А., Кондаурова Е.М., Куликова Е.А., Белокопытова И.И., Науменко В.С., 20242024Правикова П.Д., Арссан М.А., Заливина Е.А., Кондаурова Е.М., Куликова Е.А., Белокопытова И.И., Науменко В.С.Pravikova P.D., Arssan M.A., Zalivina E.A., Kondaurova E.M., Kulikova E.A., Belokopytova I.I., Naumenko V.S.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/4183

Анализ механизмов расстройства аутистического спектра (РАС) является актуальной задачей в связи с широкой и постоянно растущей распространенностью этого состояния. Исследование критических периодов нейроонтогенеза представляет интерес, поскольку манифестацию РАС нередко связывают с внутриутробными нарушениями развития головного мозга. Одна из перспективных на сегодняшний день гипотез постулирует связь патогенеза РАС с дисфункцией нейротрансмиттерных и нейротрофических систем. В настоящей работе исследована экспрессия генов ключевых рецепторов дофамина (Drd1, Drd2), нейротрофического фактора мозга (Bdnf), его рецепторов (Ntrkb2, Ngfr) и опосредующего действие BDNF транскрипционного фактора Creb1, а также дофаминового нейротрофического фактора (Cdnf) в периоды эмбриогенеза (e14 и е18) и постнатального развития (р14, р28, р60) в гиппокампе и фронтальной коре мышей BTBR с аутистизм-подобным поведением по сравнению с нейротипичной линией С57BL/6 J. У эмбрионов BTBR на 14-й день пренатального развития в гиппокампе и во фронтальной коре установлено увеличение экспрессии гена Ngfr, кодирующего рецептор p75NTR, трансдукция сигнала которого в эмбриогенезе приводит к активации апоптоза. Снижение экспрессии генов Cdnf, Bdnf и его рецептора Ntrkb2, а также дофаминовых рецепторов (Drd1, Drd2) у мышей BTBR обнаружено в постнатальный период преимущественно во фронтальной коре, при этом в гиппокампе у половозрелых особей (р60) зафиксировано падение уровня лишь мРНК Drd2. Полученные результаты позволяют предположить, что снижение в постнатальном периоде экспрессии генов Cdnf, Bdnf и Ntrkb2, а также дофаминовых рецепторов во фронтальной коре может приводить к существенным изменениям, характерным для РАС, как морфологии нейронов, так и дофаминовой нейротрансмиссии в корковых структурах мозга. Вместе с тем установленный рост экспрессии p75NTR в критический для развития гиппокампа и фронтальной коры 14-й день эмбриогенеза, возможно, является ключевым для формирования раннего аутизма.

Analysis of the mechanisms underlying autism spectrum disorder (ASD) is an urgent task due to the everincreasing prevalence of this condition. The study of critical periods of neuroontogenesis is of interest, since the manifestation of ASD is often associated with prenatal disorders of the brain development. One of the currently promising hypotheses postulates a connection between the pathogenesis of ASD and the dysfunction of neurotransmitters and neurotrophins. In this study, we investigated the expression of key dopamine receptors (Drd1, Drd2), brain-derived neurotrophic factor (Bdnf), its receptors (Ntrkb2, Ngfr) and the transcription factor Creb1 that mediates BDNF action, as well as cerebral dopamine neurotrophic factor (Cdnf) during the critical periods of embryogenesis (e14 and e18) and postnatal development (p14, p28, p60) in the hippocampus and frontal cortex of BTBR mice with autism-like behavior compared to the neurotypical C57BL/6 J strain. In BTBR embryos, on the 14th day of prenatal development, an increase in the expression of the Ngfr gene encoding the p75NTR receptor, which may lead to the activation of apoptosis, was found in the hippocampus and frontal cortex. A decrease in the expression of Cdnf, Bdnf and its receptor Ntrkb2, as well as dopamine receptors (Drd1, Drd2) was detected in BTBR mice in the postnatal period of ontogenesis mainly in the frontal cortex, while in the hippocampus of mature mice (p60), only a decrease in the Drd2 mRNA level was revealed. The obtained results suggest that the decrease in the expression levels of CDNF, BDNF-TrkB and dopamine receptors in the frontal cortex in the postnatal period can lead to significant changes in both the morphology of neurons and dopamine neurotransmission in cortical brain structures. At the same time, the increase in p75NTR receptor gene expression observed on the 14th day of embryogenesis, crucial for hippocampus and frontal cortex development, may have direct relevance to the manifestation of early autism.

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The authors declare that there are no conflicts of interest present.