Metformin treatment during neonatal period rescues hippocampal neurogenesis in the BTBR T<sup>+</sup>Itpr3<sup>tf</sup>/J mouse model of autism

Hongyu ZHONG; Lian WANG; Xiaoyu HAN; Hao XU; Xiaotang FAN

doi:10.16016/j.1000-5404.201907206

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Metformin treatment during neonatal period rescues hippocampal neurogenesis in the BTBR T⁺Itpr3^tf/J mouse model of autism

Neurosciences | 更新时间：2026-01-09

- Metformin treatment during neonatal period rescues hippocampal neurogenesis in the BTBR T⁺Itpr3^tf/J mouse model of autism
- Journal of Third Military Medical University Vol. 42, Issue 1, Pages: 1-8(2020)
- 作者机构：
  
  400038 重庆，陆军军医大学(第三军医大学)医学心理系军事认知心理学教研室
- 作者简介：
- 基金信息：
  
  the General Program of National Natural Science Foundation of China(31871043)
- DOI：10.16016/j.1000-5404.201907206
  CLC： R-332;R749.94;R977.15
- Received：26 July 2019，
  
  Revised：2019-08-31，
  
  Published：15 January 2020
- 稿件说明：
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Hongyu ZHONG, Lian WANG, Xiaoyu HAN, et al. Metformin treatment during neonatal period rescues hippocampal neurogenesis in the BTBR T⁺Itpr3^tf/J mouse model of autism[J]. Journal of Third Military Medical University, 2020, 42(1): 1-8.
DOI：

Hongyu ZHONG, Lian WANG, Xiaoyu HAN, et al. Metformin treatment during neonatal period rescues hippocampal neurogenesis in the BTBR T⁺Itpr3^tf/J mouse model of autism[J]. Journal of Third Military Medical University, 2020, 42(1): 1-8. DOI： 10.16016/j.1000-5404.201907206.

摘要

目的

研究生后早期二甲双胍治疗对BTBR T

Itpr3

/J (BTBR)自闭症模型小鼠海马神经发生的影响。

方法

利用随机数字表法将新生健康C57BL/6J (C57)、BTBR小鼠分为4组(

=5):C57生理盐水组、C57药物处理组、BTBR生理盐水组、BTBR药物处理组。生后7 d(postnatal day 7，P7)，两药物处理组予以二甲双胍(200 mg/kg)腹腔注射，每天1次，共计8次；C57及BTBR生理盐水组予以等量的生理盐水。于P14最后1次二甲双胍注射2 h后

收取脑标本进行免疫荧光染色，检测海马齿状回5-溴脱氧尿嘧啶核苷(5-bromo-2’-deoxyuridine，BrdU)、Ki67、Sox2/GFAP及Prox1的表达。

结果

在P14时，BTBR生理盐水组海马齿状回的BrdU及Ki67标记的增殖神经细胞数量比C57生理盐水组显著减少(

0.05)，而BTBR药物处理组BrdU及Ki67阳性细胞均比BTBR生理盐水组明显增多(

0.05)；BTBR生理盐水组SOX2/GFAP标记的神经干细胞和Prox1标记的新生神经元数量均比C57生理盐水组显著减少(

0.05)，而BTBR药物处理组上述两种细胞数量比BTBR生理盐水组明显增多(

0.05)。而二甲双胍早期干预并没有对C57小鼠海马神经发生产生显著影响，C57生理盐水组与C57药物处理组BrdU、Ki67、Sox2/GFAP及Prox1的表达差异无统计学意义。

结论

生后早期二甲双胍治疗显著改善BTBR小鼠海马神经发生缺陷，促进海马齿状回神经元及神经干细胞增殖。

Abstract

Objective

To investigate the effects of metformin (MET) treatment during early postnatal period on hippocampal neurogenesis of neonatal BTBR T

Itpr3

/J (BTBR) mouse model of autism.

Methods

Healthy C57BL/6J (C57) and BTBR male pups were randomly divided into C57 normal saline group (C57+NS)

C57 MET treatment group (C57+MET)

BTBR+NS

and BTBR+MET group

with 5 animals in each group. From postnatal day 7 (P7) to P14

MET (200 mg/kg) or normal saline (same volume of sterile saline solution) were intraperitoneally injected into the corresponding mice

once per day. In 2 h after the last injection on P14

all mice were sacrificed

and the brains were collected and sliced coronally. Fluorescent immunostaining was performed to detect the expression of 5-bromo-2'-deoxyuridine (BrdU)

Ki67

Sox2/GFAP and Prox1 in the dentate gyrus (DG).

Results

On P14

the numbers of BrdU-labeled cells and Ki67-labeled cells were significantly less in the DG of BTBR+NS group than the C57+NS group (

0.05)

while the numbers were obviously increased in BTBR+MET group than the C57+MET group (

0.05). Although there were remarkably less Sox2 and GFAP double-positive cells (neural stem cells) and Prox1-positive cells (newborn neurons) in BTBR+NS group than the C57+NS group (

0.05)

the 2 kinds of cells were increased obviously in BTBR+MET group than the BTBR+NS group (

0.05). However

MET treatment showed no effect on the hippocampal neurons

and there were no significant differences in the numbers of BrdU-

Ki67-

Sox2/GFAP- and Prox1-labeled cells between the C57+MET and C57+NS groups.

Conclusion

MET treatment in early postnatal period significantly improves the defects of hippocampal neurogenesis

and promotes the proliferation of hippocampal DG neurons and neural stem cells in BTBR mice.

关键词

Keywords

references

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⁰

Metformin treatment during neonatal period rescues hippocampal neurogenesis in the BTBR T+Itpr3tf/J mouse model of autism

DOI：10.16016/j.1000-5404.201907206

摘要

Abstract

关键词

Keywords

references

Metformin treatment during neonatal period rescues hippocampal neurogenesis in the BTBR T⁺Itpr3^tf/J mouse model of autism