2017 Fiscal Year Research-status Report
The roles of PIGA in epileptic encephalopathy and mental retardation
| Project/Area Number |
17K18362
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| Research Institution | Institute of Physical and Chemical Research |
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Principal Investigator |
張 王其 国立研究開発法人理化学研究所, 脳科学総合研究センター, 研究員 (20525604)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Keywords | PIGA / conditional knockout / development / epilepsy |
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| Outline of Annual Research Achievements |
We successfully deleted PIGA gene either in forebrain excitatory neurons or in inhibitory neurons by using the conditional knockout strategy. Since PIGA is an X chromosome linked gene, we could get deletion of PIGA in the entire specific cell population in male mouse, and we could get a deletion in half of the specific cell population due to x-inactivation in female mouse. (1)Deletion of PIGA in all inhibitory neurons resulted in developmental abnormality and embryo death.(2)Deletion of PIGA in all forebrain excitatory neurons resulted in embryo lethality. (3)Deletion of PIGA in all thalamus neurons didn't cause embryo death and the mutants could grow normally to adults. However, the susceptibility to kainic acid induced seizures was significantly increased in mutants.
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| Current Status of Research Progress |
Current Status of Research Progress
1: Research has progressed more than it was originally planned.
Reason
We observed much more striking phenotypes in the PIGA conditional knockout mice than what we previously expected. When PIGA was specifically deleted in the inhibitory neurons, the embryo stopped development on E7. When PIGA was deleted in forebrain excitatory neurons, the E13.5 embryo showed neural tube defects and anencephaly, and the embryo failed to continue to develop to birth. When PIGA was deleted in thalamus excitatory neurons, the mutants could develop normally to adults. Further analysis of the thalamus specific PIGA deletion mice revealed that kainic acid induced more severe seizure activity, both physically and behaviorally, on these mutants.
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| Strategy for Future Research Activity |
As planned, we will continue to assay the histological and physiological changes in our conditional mutated mice in more details. In addition, we will express the exogenous PIGA in our interested neural circuits by AAV virus injection, so that we can investigate the rescue effects of the gene therapy.
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| Causes of Carryover |
We will need to maintaining the conditional knockout mice; We will need to prepare EEG recording and silicon probe recording related items; We will need to prepare AAV virus packaging related items. We will need language editing for our publication of current project.
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