Role of scaffolding protein Homer protein homolog 1b and 1c in a <italic style="font-style: italic">CTNND2<sup>-/- </sup></italic>mouse model of autism

Zhang Hanhong; Wang Yan; Mingqi Lü; Nie Ying; Cai Jinwen; Wang Chuxuan; Li Yingbo

doi:10.13406/j.cnki.cyxb.003472

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Role of scaffolding protein Homer protein homolog 1b and 1c in a CTNND2^-/-mouse model of autism

Basic research | 更新时间：2025-10-22

- Role of scaffolding protein Homer protein homolog 1b and 1c in a CTNND2^-/-mouse model of autism
- Journal of Chongqing Medical University Vol. 49, Issue 4, Pages: 409-414(2024)
- 作者机构：
  
  1.重庆医科大学神经科学研究中心，重庆 400016
  2.重庆医科大学实验教学管理中心人体机能实验室，重庆 400016
- 作者简介：
- 基金信息：
- DOI：10.13406/j.cnki.cyxb.003472
  CLC： R338
- Received：28 February 2024，
  
  Revised：2024-03-04，
  
  Accepted：06 March 2024，
  
  Published：28 April 2024
- 稿件说明：
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张翰鸿,王岩,吕明其,等.Homer1b/c“支架”在CTNND2^-/-自闭症模型鼠中的作用研究[J].重庆医科大学学报,2024,49(4):409-414.

Zhang Hanhong,Wang Yan,Lü Mingqi,et al.Role of scaffolding protein Homer protein homolog 1b and 1c in a CTNND2^-/-mouse model of autism[J].Journal of Chongqing Medical University,2024,49(4):409-414.
张翰鸿,王岩,吕明其,等.Homer1b/c“支架”在CTNND2^-/-自闭症模型鼠中的作用研究[J].重庆医科大学学报,2024,49(4):409-414. DOI： 10.13406/j.cnki.cyxb.003472.

Zhang Hanhong,Wang Yan,Lü Mingqi,et al.Role of scaffolding protein Homer protein homolog 1b and 1c in a CTNND2^-/-mouse model of autism[J].Journal of Chongqing Medical University,2024,49(4):409-414. DOI： 10.13406/j.cnki.cyxb.003472.

摘要

目的

观察

CTNND2

-/-

自闭症模型鼠前额叶皮层中支架蛋白荷马1b/c（homer protein homolog 1b and 1c，Homer1b/c）与三磷酸肌醇受体（inositol 1，4，5-trisphosphate receptor，IP3R）、代谢型谷氨酸受体5（metabotropic glutamate receptor 5，mGluR5）和香克3蛋白（sh3 and multiple ankyrin repeat domains 3，Shank3）蛋白相关复合体的变化；前额叶皮层中常见氨基酸的变化，发现自闭症模型鼠中可能参与疾病发生的关键靶点。

方法

蛋白免疫印迹法（Western blot，WB）法检测

CTNND2

-/-

自闭症模型鼠前额叶皮层中支架蛋白Homer1b/c、突触后密度蛋白-95（postsynaptic density protein 95，PSD-95）、突触素蛋白（synaptophysin，SYP）、囊泡谷氨酸转运体1（vesicular glutamate transporter 1，vGluT1）的表达的变化；通过免疫荧光（immunofluorescence，IF）观察Homer1b/c与IP3R、mGluR5和Shank3蛋白的表达与共定位；免疫共沉淀（co-immunoprecipitation，CO-IP）技术分别观察Homer1b/c与IP3R、mGluR5或Shank3结合的变化；使用液相色谱（liquid chromatography，LC）观察前额叶皮层中常见氨基酸的变化。

结果

与对照组相比，

CTNND2

-/-

模型鼠前额叶皮层中Homer1b/c（

=0.003）、PSD-95（

=0.003）以及SYP蛋白（

=0.046）的表达均明显降低；同时，Homer1b/c与IP3R、mGluR5、Shank3蛋白相互之间结合减少；前额叶皮层中常见的兴奋性神经递质谷氨酸（glutamate，Glu）和抑制性神经递质γ-氨基丁酸（γ-aminobutyric acid，GABA）的表达无明显变化（

=0.366，

=0.355），组氨酸（histidine，His）（

=0.036），酪氨酸（tyrosine，Tyr）（

=0.030）表达则明显增高。

结论

CTNND2

-/-

自闭症模型鼠中Homer1b/c蛋白低表达，同时Homer1b/c与IP3R、Shank3、mGluR5蛋白复合物的形成减少，并推测低表达的Homer1b/c可能是导致自闭症神经元突触异常发育的关键靶点。

Abstract

Objective

To observe the changes in scaffolding protein Homer protein homolog 1b and 1c（Homer1b/c），inositol 1，4，5-trisphosphate receptor（IP3R），metabotropic glutamate receptor 5（mGluR5），sh3 and multiple ankyrin repeat domains 3（Shank3） protein-related complexes，and common amino acids in the prefrontal cortex of

CTNND2

-/-

mice with autism，and to investigate the key targets that may be involved in the development of the disease in mice with autism.

Methods

Western blot（WB） was used to measure the changes in the protein expression levels of Homer1b/c，postsynaptic density-95（PSD-95），synaptophysin（SYP），and vesicular glutamate transporter 1（vGluT1） in the prefrontal cortex of

CTNND2

-/-

mice with autism；immunofluorescent（IF） staining was used to investigate the expression and colocalization of Homer1b/c with IP3R，mGluR5，or Shank3 proteins；co-immunoprecipitation（CO-IP） was used to observe the binding of Homer1b/c to IP3R，mGluR5 or Shank3；liquid chromatography（LC） was used to analyze the changes in common amino acids in the prefrontal cortex of mice.

Results

Compared with the control group，the

CTNND2

-/-

model mice had significant reductions in the expression of Homer1b/c（

=0.003），PSD-95（

=0.003），and SYP（

=0.046） in the prefrontal cortex and a significant reduction in the binding of Homer1b/c to IP3R，mGluR5，and Shank3 proteins，and there were no significant changes in the expression levels of the common excitatory neurotransmitter glutamate and the inhibitory neurotransmitter γ-aminobutyric acid in the prefrontal cortex（

=0.366 and 0.355），while there were significant increases in the expression levels of histidine（

=0.036） and tyrosine（

=0.030）.

Conclusion

There is low expression of Homer1b/c protein in the

CTNND2

-/-

mouse model of autism，and there is a reduction in the formation of Homer1b/c complexes with IP3R，Shank3，and mGluR5 proteins. It is speculated that low-expression Homer1b/c may be a key target for abnormal synaptic development in autism.

关键词

Keywords

references

Li XY ， Naveed Iqbal Qureshi M ， Laplante DP ， et al . Decreased amygdala-sensorimotor connectivity mediates the association between prenatal stress and broad autism phenotype in young adults：project Ice Storm [J ] . Stress ， 2024 ， 27 （ 1 ）： 2293698 ．

Mohapatra AN ， Wagner S . The role of the prefrontal cortex in social interactions of animal models and the implications for autism spectrum disorder [J ] . Front Psychiatry ， 2023 ， 14 ： 1205199 .

Xu M ， Wang LY ， Wang Y ， et al . Melatonin ameliorates sleep-wake disturbances and autism-like behaviors in the Ctnnd2 knock out mouse model of autism spectrum disorders [J ] . Genes Brain Behav ， 2023 ， 22 （ 4 ）： e12852 .

Wu XQ ， Su N ， Fei Z ， et al . Homer signaling pathways as effective therapeutic targets for ischemic and traumatic brain injuries and retinal lesions [J ] . Neural Regen Res ， 2022 ， 17 （ 7 ）： 1454 - 1461 .

Huang M ， Pu SF ， Jiang W ， et al . Deficiency of SHANK3 isoforms impairs thermal hyperalgesia and dysregulates the expression of postsynaptic proteins in the spinal cord [J ] . Neurosci Res ， 2021 ， 163 ： 26 - 33 .

Wang ML ， Pan W ， Xu Y ， et al . Microglia-mediated neuroinflammation：a potential target for the treatment of cardiovascular diseases [J ] . J Inflamm Res ， 2022 ， 15 ： 3083 - 3094 .

Parellada M ， Andreu-Bernabeu Á ， Burdeus M ， et al . In search of biomarkers to guide interventions in autism spectrum disorder：a systematic review [J ] . Am J Psychiatry ， 2023 ， 180 （ 1 ）： 23 - 40 .

Brister D ， Rose S ， Delhey L ， et al . Metabolomic signatures of autism spectrum disorder [J ] . J Pers Med ， 2022 ， 12 （ 10 ）： 1727 .

Lominac KD ， Oleson EB ， Pava M ， et al . Distinct roles for different Homer1 isoforms in behaviors and associated prefrontal cortex function [J ] . J Neurosci ， 2005 ， 25 （ 50 ）： 11586 - 11594 .

Zeng X ， Pan ZG ， Shao Y ， et al . SKF-96365 attenuates toxin-induced neuronal injury through opposite regulatory effects on Homer1a and Homer1b/c in cultured rat mesencephalic cells [J ] . Neurosci Lett ， 2013 ， 543 ： 183 - 188 .

Jung S ， Park M . Shank postsynaptic scaffolding proteins in autism spectrum disorder：mouse models and their dysfunctions in behaviors，synapses，and molecules [J ] . Pharmacol Res ， 2022 ， 182 ： 106340 .

Defresne P ， Mottron L . Clinical Situations in Which the Diagnosis of Autism is Debatable: An Analysis and Recommendations Situations cliniques ou le diagnostic d'autisme apporte peu : notre analyse，et nos recommandations [J ] . Can J Psychiatry Rev Can De Psychiatr ， 2021 ， 67 （ 3 ）： 331 - 335 .

Coley AA ， Gao WJ . PSD95：a synaptic protein implicated in schizophrenia or autism? [J ] . Prog Neuropsychopharmacol Biol Psychiatry ， 2018 ， 82 ： 187 - 194 .

Feyder M ， Karlsson RM ， Mathur P ， et al . Association of mouse Dlg4（PSD-95） gene deletion and human DLG4 gene variation with phenotypes relevant to autism spectrum disorders and Williams' syndrome [J ] . Am J Psychiatry ， 2010 ， 167 （ 12 ）： 1508 - 1517 .

Cheng DM ， Hoogenraad CC ， Rush J ， et al . Relative and absolute quantification of postsynaptic density proteome isolated from rat forebrain and cerebellum [J ] . Mol Cell Proteomics ， 2006 ， 5 （ 6 ）： 1158 - 1170 .

Cao L ， Tian Y ， Jiang Y ， et al . Down-regulation of Homer1b/c protects against chemically induced seizures through inhibition of mTOR signaling [J ] . Cell Physiol Biochem ， 2015 ， 35 （ 4 ）： 1633 - 1642 .

Guo ZY ， Zhang YH ， Xie GQ ， et al . Down-regulation of Homer1 attenuates t-BHP-induced oxidative stress through regulating calcium homeostasis and ER stress in brain endothelial cells [J ] . Biochem Biophys Res Commun ， 2016 ， 477 （ 4 ）： 970 - 976 .

Chen FH ， Polsinelli B ， Nava N ， et al . Structural plasticity and molecular markers in hippocampus of male rats after acute stress [J ] . Neuroscience ， 2020 ， 438 ： 100 - 115 .

Marchi M ， Grilli M . Presynaptic nicotinic receptors modulating neurotransmitter release in the central nervous system：functional interactions with other coexisting receptors [J ] . Prog Neurobiol ， 2010 ， 92 （ 2 ）： 105 - 111 .

Ristori MV ， Quagliariello A ， Reddel S ， et al . Autism，gastrointestinal symptoms and modulation of gut microbiota by nutritional interventions [J ] . Nutrients ， 2019 ， 11 （ 11 ）： 2812 .

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Role of scaffolding protein Homer protein homolog 1b and 1c in a CTNND2-/- mouse model of autism

DOI：10.13406/j.cnki.cyxb.003472

摘要

Abstract

关键词

Keywords

references

Role of scaffolding protein Homer protein homolog 1b and 1c in a CTNND2^-/-mouse model of autism