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Involvement of abnormal Q/R editing of GluA2 subunit of Ca2+ permeable a-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid receptor (AMPA) receptor in ketamine-induced cognitive impairment.
China (IFMSA-China) - China Medical University, Shenyang
Department of Forensic Pathology
Type of Research Project
- Basic science
What is the background of the project?
The cognitive impairment caused by ketamine abuse is closely related to Ca2+ influx mediated by calcium permeable AMPA (CP-AMPA) receptor in the brain, but the mechanism is unclear so far. The Q/R editing of AMPA receptor refers to the change of codon 607 of GluA2 subunit precursor mRNA from glutamine (Q) to arginine (R), which can lead to synaptic plasticity injury through regulating Ca2+ permeability of CP-AMPA. The adenosine deaminases acting on RNA (ADAR2) is a key enzyme in Q/R editing and is bidirectionally regulated by peptidyl-prolyl isomerase PIN1 and E3 Ubiquitin-protein ligase WWP2. Therefore, we speculate that ketamine abuse may cause abnormal bidirectional regulation of PIN1/WWP2 to ADAR2 in the brain that decreases the nucleus entry of ADAR2, the Q/R editing level of GluA2 subunit decrease, and the expression of CP-AMPA increase that causes intracellular calcium overload, which ultimately leads to synaptic damage and cognitive impairment.
What is the aim of the project?
The aim of the project is to explore the potential changes of ketamine abuse induced cerebral CP-AMPA receptors abnormal expression and learning and memory impairments and provide theoretical basis and new ideas for the study of molecular mechanism of cognitive impairment caused by ketamine abuse.
What techniques and methods are used?
Adult mice (C57BL/6) and SH-SY5Y cell line were used in our project in in-vivo and in-vitro experiments. Animal models were established by acute and chronic ketamine intraperitoneal injection. SH-SY5Y cells were treated by serial ketamine concentrations. Behavioral tests were performed after acute and chronic ketamine administration. The levels of AMPA receptor subunit GluA1, A2 and A3, ADAR2, Pin1, WWP2, Caspase-3, intracellular Ca2+, TdT-mediated dUTP Nick-End Labeling (TUNEL), Fluoro Jade-C, flow cytometry, were measured.
What is the role of the student?
- The student will mainly observe
- The student will observe the practical experiments but will be highly involved in the analysis of the results
- The tasks of the student will be performed on his/her own
- The tasks will be done under supervision
What are the tasks expected to be accomplished by the student?
Students are expected to participated in work in two main areas. For one hand, students should master the skills of cell culture and molecular biology experiments like protein and mRNA extraction and Western Blot. Meanwhile, students will have access to learn laboratory animal feeding and molecular biology and histological experiments of brain tissues. Skills of behavior tests of animal models are also required, such as open fields test, Morries water maze test, Radial aam meza test, Elevated plus maze, Y maze test and Novel objects recognition tests.
Will there be any theoretical teaching provided (preliminary readings, lectures, courses, seminars etc)
Some lectures and seminars will be available for them.directed by Prof. Wu Xu.
What is expected from the student at the end of the research exchange? What will be the general outcome of the student?
- The student will prepare a scientific report
What skills are required of the student? Is there any special knowledge or a certain level of studies needed?
The knowledge of Molecular biology, Cell biology and Histology is required. Honesty and integrity, diligence and good team work spirit is required. Apart from this, students who have biological, pathological or histological knowledge, trainings or background is recommended
Are there any legal limitations in the student’s involvement
Type of students accepted
This project accepts: - Graduated students (less than 6 months)
- Long-term ketamine administration causes Tau protein phosphorylation and Tau protein-dependent AMPA receptor reduction in the hippocampus of mice. Toxicol Lett. 2019; 15;315:107-115. doi: 10.1016/j.toxlet.2019.08.023.
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