2019 Fiscal Year Final Research Report
The roles of PIGA in epileptic encephalopathy and mental retardation
| Project/Area Number |
17K18362
|
|---|
| Research Category |
Grant-in-Aid for Young Scientists (B)
|
| Allocation Type | Multi-year Fund |
|---|
| Research Field |
Neurology
Pathological medical chemistry
|
|---|
| Research Institution | University of Tsukuba (2018-2019)
Institute of Physical and Chemical Research (2017) |
|---|
Principal Investigator |
zhang qi 筑波大学, 人間系, 助教 (20525604)
|
|---|
| Project Period (FY) |
2017-04-01 – 2020-03-31
|
| Keywords | PIGA, / epilepsy, / mental retardation, / ataxia, / hippocampus, / synapse, / E/I balance, / GPI-anchor |
|---|
| Outline of Final Research Achievements |
Global PIGA knockout causes embryo lethality. By using conditional knockout system, we successfully obtained mouse lines with the ablation of PIGA specifically in inhibitory neurons(IKO), in forebrain excitatory neurons(EKO) or in thalamus neurons(TKO).The behavioral, EEG, histology and electrophysiology analysis showed that IKO and EKO but not TKO mice performed poorly in learning and memory task. IKO and EKO demonstrated obvious ataxia. It is notable that the susceptibility to kainic acid induced seizures was significantly increased in all the three types of mutants. The synaptic density was changed in specific hippocampal subregions of all the mutants. There was a significant E/I balance change in IKO and EKO mice. In addition, AAV virus mediated PIGA expression in hippocampus could significantly suppress Kainic acid induced seizure in IKO and EKO. We elucidated that the synapse abnormality in specific subregions of hippocampus plays important roles underlying PIGA encephalopathy.
|
| Free Research Field |
神経分子病態学
|
| Academic Significance and Societal Importance of the Research Achievements |
Patients with PIGA mutations suffer from intractable epileptic seizures and mental retardation.Our study provided important clues of molecular and circuit mechanisms underlying PIGA encephalopathy,and will help to develop effective gene therapy to treat brain disease caused by GPI-anchor deficits.
|
