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Vitamin D3 improves iminodipropionitrile-induced tic-like behavior in rats through regulation of GDNF/c-Ret signaling activity

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Abstract

Children with chronic tic disorders (CTD), including Tourette syndrome (TS), have significantly reduced serum 25-hydroxyvitamin D [25(OH)D]. While vitamin D3 supplementation (VDS) may reduce tic symptoms in these children, its mechanism is unclear. The study aim was to investigate the effects and mechanisms of vitamin D deficiency (VDD) and VDS on TS model behavior. Forty 5-week-old male Sprague–Dawley rats were randomly divided into (n = 10 each): control, TS model, TS model with VDD (TS + VDD), or TS model with VDS (TS + VDS; two intramuscular injections of 20,000 IU/200 g) groups. The VDD model was diet-induced (0 IU vitamin D/kg); the TS model was iminodipropionitrile (IDPN)-induced. All groups were tested for behavior, serum and striatal 25(OH)D and dopamine (DA), mRNA expressions of vitamin D receptor (VDR), glial cell line-derived neurotrophic factor (GDNF), protooncogene tyrosine–protein kinase receptor Ret (c-Ret), and DA D1 (DRD1) and D2 (DRD2) receptor genes in the striatum. TS + VDD had higher behavior activity scores throughout, and higher total behavior score at day 21 compared with TS model. In contrast, day 21 TS + VDS stereotyped behavior scores and total scores were lower than TS model. The serum 25(OH)D in TS + VDD was < 20 ng/mL, and lower than control. Striatal DA of TS was lower than control. Compared with TS model, striatal DA of TS + VDD was lower, while in TS + VDS it was higher than TS model. Furthermore, mRNA expression of VDR, GDNF, and c-Ret genes decreased in TS model, and GDNF expression decreased more in TS + VDD, while TS + VDS had higher GDNF and c-Ret expressions. VDD aggravates, and VDS ameliorates tic-like behavior in an IDPN-induced model. VDS may upregulate GDNF/c-Ret signaling activity through VDR, reversing the striatal DA decrease and alleviating tic-like behavior.

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Data availability

The original data supporting the conclusions of this article will be made available on request.

Code availability

Not applicable.

Abbreviations

CTDs:

Chronic tic disorders

TS:

Tourette syndrome

CSTC:

Cortico-striato-thalamo-cortical

DRD2:

Dopamine D2 receptor

DRD1:

Dopamine D1 receptor

VD:

Vitamin D

25[OH]D:

25-Hydroxyvitamin D

VDR:

Vitamin D receptor

TH:

Enzyme–tyrosine hydroxylase

GDNF:

Glial cell line-derived neurotrophic factor

c-Ret:

Protooncogene tyrosine–protein kinase receptor Ret

VDS:

Vitamin D3 supplementation

VDD:

Vitamin D deficiency

IDPN:

Iminodipropionitrile

ELISA:

Enzyme-linked immunosorbent assay

qPCR:

Quantitative real-time polymerase chain reaction

SD:

Standard deviation

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Funding

Talent Reserve Program (TRP) of the First Hospital of Jilin University (JDYY-TRP-2024011) and the 2021 Pediatric Endocrinology Research Foundation for Young and Middle-aged Physicians (Z-2019–41-2101–01) sponsored this work.

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Authors and Affiliations

  1. Department of Developmental and Behavioral Pediatrics, Children’s Hospital, The First Hospital of Jilin University, Changchun, Jilin, 130021, China

    Hong-Hua Li, Xi-Fei Wang, Bing Wang & Fei-Yong Jia

  2. School of Public Health, Jilin University, Changchun, Jilin Province, China

    Hong-Hua Li

  3. The Child Health Clinical Research Center of Jilin Province, Changchun, China

    Hong-Hua Li, Xi-Fei Wang, Bing Wang & Fei-Yong Jia

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  1. Hong-Hua Li
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  2. Xi-Fei Wang
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  3. Bing Wang
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  4. Fei-Yong Jia
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Contributions

HL and FJ designed the research and provided funding; HL and XW drafted the manuscript; BW and XW participated in the process of this research and collected the data; HL and FJ contributed to the study concept and manuscript revision. All authors contributed to the article and approved the submitted version.

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Correspondence to Fei-Yong Jia.

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The authors declare that the research was carried out without any commercial or financial commitments that may become potential conflicts of interest.

Ethical approval

The study was approved by the Ethics Committee of Chongqing Western Biological Experimental Animal Ethics Committee (No: WST20220303S0401231[001]; Date of approval: March 3, 2022).

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All authors contributed to the article and approved the submitted version.

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Li, HH., Wang, XF., Wang, B. et al. Vitamin D3 improves iminodipropionitrile-induced tic-like behavior in rats through regulation of GDNF/c-Ret signaling activity. Eur Child Adolesc Psychiatry (2024). https://doi.org/10.1007/s00787-024-02376-z

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