mGluR1/IP3/ERK signaling pathway regulates vestibular compensation in ON UBCs of the cerebellar flocculus

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2023-08-25 DOI:10.1111/cns.14419

Dan Liu, Jun Wang, E. Tian, Jingyu Chen, Weijia Kong, Yisheng Lu, Sulin Zhang

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Abstract

Aims

To investigate the role of mGluR1α in cerebellar unipolar brush cells (UBC) in mediating vestibular compensation (VC), using mGluR1α agonist and antagonist to modulate ON UBC neurons, and explore the mGluR1/IP3/extracellular signal-regulated kinase (ERK) signaling pathway.

Methods

First, AAV virus that knockdown ON UBC (mGluR1α) were injected into cerebellar UBC by stereotactic, and verified by immunofluorescence and western blot. The effect on VC was evaluated after unilateral labyrinthectomy (UL). Second, saline, (RS)-3,5-dihydroxyphenylglycine (DHPG), and LY367385 were injected into tubes implanted in rats at different time points after UL separately. The effect on ON UBC neuron activity was evaluated by immunofluorescence. Then, Phosphoinositide (PI) and p-ERK1/2 levels of mGluR1α were analyzed by ELISA after UL. The protein levels of p-ERK and total ERK were verified by western blot. In addition, the effect of mGluR1α activation or inhibition on VC-related behavior was observed.

Results

mGluR1α knockdown induced VC phenotypes. DHPG increased ON UBC activity, while LY367385 reduced ON UBC activity. DHPG group showed an increase in PI and p-ERK1/2 levels, while LY367385 group showed a decrease in PI and p-ERK1/2 levels in cerebellar UBC of rats. The western blot results of p-ERK and total ERK confirm and support the observations. DHPG alleviated VC-related behavior phenotypes, while LY367385 exacerbated vestibular decompensation-like behavior induced by UL.

Conclusion

mGluR1α activity in cerebellar ON UBC is crucial for mediating VC through the mGluR1/IP3/ERK signaling pathway, which affects ON UBC neuron activity and contributes to the pathogenesis of VC.

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mGluR1/IP3/ERK信号通路调节小脑絮状体ON UBC的前庭补偿

目的研究小脑单极刷状细胞（UBC）中的mGluR1α在介导前庭代偿（VC）中的作用，利用mGluR1α激动剂和拮抗剂调节ON UBC神经元，并探索mGluR1/IP3/细胞外信号调节激酶（ERK）信号通路。方法首先，通过立体定向法将敲除 ON UBC（mGluR1α）的 AAV 病毒注入小脑 UBC，并通过免疫荧光和 Western blot 验证。评估了单侧迷走神经切除术（UL）对VC的影响。其次，在单侧迷走神经切除术（UL）后的不同时间点，将生理盐水、(RS)-3,5-二羟基苯甘氨酸（DHPG）和 LY367385 分别注入植入大鼠体内的管中。免疫荧光法评估了对 ON UBC 神经元活性的影响。然后，用酶联免疫吸附法分析了UL后mGluR1α的磷酸肌酸（PI）和p-ERK1/2水平。蛋白水平。此外，还观察了激活或抑制 mGluR1α 对 VC 相关行为的影响。结果 mGluR1α 敲除会诱导 VC 表型。DHPG 增加了 ON UBC 的活性，而 LY367385 则降低了 ON UBC 的活性。DHPG 组大鼠小脑 UBC 的 PI 和 p-ERK1/2 水平升高，而 LY367385 组大鼠小脑 UBC 的 PI 和 p-ERK1/2 水平降低。p-ERK和总ERK的Western印迹结果证实并支持了上述观察结果。DHPG 可减轻与 VC 相关的行为表型，而 LY367385 则会加剧 UL 诱导的前庭失代偿样行为。结论小脑ON UBC中的mGluR1α活性是通过mGluR1/IP3/ERK信号通路介导VC的关键，而mGluR1/IP3/ERK信号通路会影响ON UBC神经元的活性并导致VC的发病。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.