The Pin1-CaMKII-AMPA Receptor Axis Regulates Epileptic Susceptibility

被引：10

作者：

Hou, Xiaojun ^{[1
,2
]}

Yang, Fan ^{[1
]}

Li, Angcheng ^{[1
]}

Zhao, Debao ^{[1
]}

Ma, Nengjun ^{[1
]}

Chen, Linying ^{[1
,3
]}

Lin, Suijin ^{[1
]}

Lin, Yuanxiang ^{[3
]}

Wang, Long ^{[1
]}

Yan, Xingxue ^{[1
]}

Zheng, Min ^{[1
]}

Lee, Tae Ho ^{[1
]}

Zhou, Xiao Zhen ^{[4
,5
]}

Lu, Kun Ping ^{[4
,5
,6
]}

Liu, Hekun ^{[1
]}

机构：

[1] Fujian Med Univ, Sch Basic Med Sci, Inst Translat Med, Fujian Key Lab Translat Res Canc & Neurodegenerat, Fuzhou 350108, Fujian, Peoples R China

[2] Fujian Med Univ, Fuzhou Childrens Hosp, Fuzhou 350005, Fujian, Peoples R China

[3] Fujian Med Univ, Affiliated Hosp 1, Fuzhou 350009, Fujian, Peoples R China

[4] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Div Translat Therapeut, Boston, MA 02115 USA

[5] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Canc Res Inst, Boston, MA 02115 USA

[6] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

来源：

CEREBRAL CORTEX | 2021年 / 31卷 / 06期

基金：

美国国家卫生研究院;

关键词：

AMPA receptor; CaMKII; epilepsy; Pin1; prefrontal cortex; PROLYL-ISOMERASE PIN1; PHOSPHORYLATION SITE; KNOCKOUT MICE; ISOMERIZATION; DISEASE; MODEL; TAU; IDENTIFICATION; PROTEINS; GLUR1;

D O I：

10.1093/cercor/bhab004

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Pint is a unique isomerase that regulates protein conformation and function after phosphorylation. Pint aberration contributes to some neurological diseases, notably Alzheimer's disease, but its role in epilepsy is not fully understood. We found that Pin1-deficient mice had significantly increased seizure susceptibility in multiple chemical inducing models and developed age-dependent spontaneous epilepsy. Electrophysiologically, Pin1 ablation enhanced excitatory synaptic transmission to prefrontal cortex (PFC) pyramidal neurons without affecting their intrinsic excitability. Biochemically, Pint ablation upregulated AMPA receptors and GluA1 phosphorylation by acting on phosphorylated CaMKII. Clinically, Pint was decreased significantly, whereas phosphorylated CaMKII and GluA1 were increased in the neocortex of patients with epilepsy. Moreover, Pint expression restoration in the PFC of Pin1-deficient mice using viral gene transfer significantly reduced phosphorylated CaMKII and GluA1 and effectively suppressed their seizure susceptibility. Thus, Pin1-CaMKII-AMPA receptors are a novel axis controlling epileptic susceptibility, highlighting attractive new therapeutic strategies.

引用

页码：3082 / 3095

页数：14

共 62 条

[1] Function and regulation of tau conformations in the development and treatment of traumatic brain injury and neurodegeneration [J].