The Role and Mechanism of AMIGO3 in the Formation of Aberrant Neural Circuits After Status Convulsion in Immature Mice.

Xue Li,Hengsheng Chen,Li Cheng,Xiaojie Song,Dishu Huang,Zhixu Fang,Li Jiang,Yanan Pan,Jianxiong Gui,Hanyu Luo

doi:10.3389/fnmol.2021.748115

Abstract

Leucine rich repeat and immunoglobulin-like domain-containing protein 1 (Lingo-1) has gained considerable interest as a potential therapy for demyelinating diseases since it inhibits axonal regeneration and myelin production. However, the results of clinical trials targeted at Lingo-1 have been unsatisfactory. Amphoterin-induced gene and open reading frame-3 (AMIGO3), which is an analog of Lingo-1, might be an alternative therapeutic target for brain damage. In the present study, we investigated the effects of AMIGO3 on neural circuits in immature mice after status convulsion (SC) induced by kainic acid. The expression of both AMIGO3 and Lingo-1 was significantly increased after SC, with levels maintained to 20 days after SC. Following SC, transmission electron microscopy revealed the impaired microstructure of myelin sheaths and Western blot analysis showed a decrease in myelin basic protein expression, and this damage was alleviated by downregulation of AMIGO3 expression. The ROCK/RhoA signaling pathway was inhibited at 20 days after SC by downregulating AMIGO3 expression. These results indicate that AMIGO3 plays important roles in seizure-induced damage of myelin sheaths as well as axon growth and synaptic plasticity via the ROCK/RhoA signaling pathway.

Highlights

Seizures in children are more likely to be classified as status convulsion (SC) with adverse neurological outcomes than adults (Reinholdson et al, 2015)
Western blot analysis showed that the expression of both like domain-containing protein 1 (Lingo-1) and AMIGO3 proteins increased in the cortex after SC compared with the levels detected in the control group at the same age (Figures 1A–C)
We found that AMIGO3 protein levels showed a similar pattern of increasing expression as that observed for Lingo-1, with peak expression at day 20 after SC

Summary

Introduction

Seizures in children are more likely to be classified as status convulsion (SC) with adverse neurological outcomes than adults (Reinholdson et al, 2015). We demonstrated that the myelin sheath, axons and synaptic structure are damaged after SC in immature rats, leading to increased susceptibility to seizures, epilepsy and learning and memory dysfunction in the chronic phase (Song et al, 2018). Learning and memory function have been shown to improve following attenuation of the injury to axons and myelin sheaths (Ye et al, 2013; He et al, 2017; Song et al, 2018) These results suggest that the formation of abnormal neural circuits may be the main cause of learning and memory dysfunction and secondary epilepsy after SC. It has been suggested that additional mechanisms are involved in the pathogenesis of axonal and myelin injury

Methods

Results

Conclusion