MiR-219 Protects Against Seizure in the Kainic Acid Model of Epilepsy.
Emerging evidence indicates that certain microRNAs (miRNAs) play important roles in epileptogenesis. MiR-219 is a brain-specific miRNA and has been shown to negatively regulate the function of N-methyl-D-aspartate (NMDA) receptors by targeting Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)γ. Herein, we found that the level of miR-219 was decreased in both the kainic acid (KA)-induced epilepsy model and in cerebrospinal fluid specimens of epilepsy patients. Importantly, silencing of miR-219 by its antagomir in vivo resulted in seizure behaviors, abnormal cortical electroencephalogram (EEG) recordings in the form of high-amplitude and high-frequency discharges, and increased levels of CaMKIIγ and an NMDA receptor component, NR1, in a pattern similar to that found in KA-treated mice. Moreover, treatments with the miR-219 agomir in vivo alleviated seizures, abnormal EEG recordings, and decreased levels of CaMKIIγ and NR1 in KA-treated mice. Furthermore, treatment with MK-801, an antagonist of NMDA receptors, significantly alleviated abnormal EEG recordings induced by miR-219 antagomir. Together, these results demonstrate that miR-219 plays a crucial role in suppressing seizure formation in experimental models of epilepsy through modulating the CaMKII/NMDA receptor pathway and that miR-219 supplement may be a potential anabolic strategy for ameliorating epilepsy.
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen, 361005, Fujian Province, China.|Department of Basic Medicine, Medical College, Xiamen University, Xiamen, 361005, Fujian Province, China.
Honghua
H
Zheng
Department of Neurology, Affiliated Zhongshan Hospital, Xiamen University, Xiamen, 361004, Fujian Province, China.
Rong
R
Tang
Epilepsy Research Center, Department of Neurosurgery, Affiliated Chenggong Hospital, Xiamen University, Xiamen, 361004, Fujian Province, China.
Yi
Y
Yao
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen, 361005, Fujian Province, China.|Department of Basic Medicine, Medical College, Xiamen University, Xiamen, 361005, Fujian Province, China.
Zhilin
Z
Ji
Department of Neurology, Affiliated Zhongshan Hospital, Xiamen University, Xiamen, 361004, Fujian Province, China.
Yuanyuan
Y
Cao
Department of Neurology, Affiliated Zhongshan Hospital, Xiamen University, Xiamen, 361004, Fujian Province, China.
Zhaoji
Z
Liu
Department of Neurology, Affiliated Zhongshan Hospital, Xiamen University, Xiamen, 361004, Fujian Province, China.
Feng
F
Peng
Department of Neurology, Affiliated Zhongshan Hospital, Xiamen University, Xiamen, 361004, Fujian Province, China.
Wenjie
W
Wang
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen, 361005, Fujian Province, China.
Dan
D
Can
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen, 361005, Fujian Province, China.
Huiqin
H
Xing
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen, 361005, Fujian Province, China.
Guojun
G
Bu
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen, 361005, Fujian Province, China.
Huaxi
H
Xu
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen, 361005, Fujian Province, China. yunzhang@xmu.edu.cn.
Yun-Wu
YW
Zhang
Department of Neurology, Affiliated Zhongshan Hospital, Xiamen University, Xiamen, 361004, Fujian Province, China. zwh610547@xmu.edu.cn.
Weihong
W
Zheng
D000293:Adolescent; D000328:Adult; D000818:Animals; D001921:Brain / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000134:cerebrospinal fluid / Q000378:metabolism*; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012640:Seizures / Q000134:cerebrospinal fluid* / Q000175:diagnosis / Q000378:metabolism; D055815:Young Adult
C578248:MIRN219 microRNA, human; C000609357:MIRN219 microRNA, mouse; D035683:MicroRNAs; D016194:Receptors, N-Methyl-D-Aspartate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
CaMKIIγ; Epilepsy; Kainic acid; MiR-219; NMDA receptor