Silencing microRNA-134 produces neuroprotective and prolonged seizure-suppressive effects.
Temporal lobe epilepsy is a common, chronic neurological disorder characterized by recurrent spontaneous seizures. MicroRNAs (miRNAs) are small, noncoding RNAs that regulate post-transcriptional expression of protein-coding mRNAs, which may have key roles in the pathogenesis of neurological disorders. In experimental models of prolonged, injurious seizures (status epilepticus) and in human epilepsy, we found upregulation of miR-134, a brain-specific, activity-regulated miRNA that has been implicated in the control of dendritic spine morphology. Silencing of miR-134 expression in vivo using antagomirs reduced hippocampal CA3 pyramidal neuron dendrite spine density by 21% and rendered mice refractory to seizures and hippocampal injury caused by status epilepticus. Depletion of miR-134 after status epilepticus in mice reduced the later occurrence of spontaneous seizures by over 90% and mitigated the attendant pathological features of temporal lobe epilepsy. Thus, silencing miR-134 exerts prolonged seizure-suppressant and neuroprotective actions; determining whether these are anticonvulsant effects or are truly antiepileptogenic effects requires additional experimentation.
Department of Physiology and Medical Physics and Centre for Study of Neurological Disorders, Royal College of Surgeons in Ireland, Dublin, Ireland.
Eva M
EM
Jimenez-Mateos
Tobias
T
Engel
Paula
P
Merino-Serrais
Ross C
RC
McKiernan
Katsuhiro
K
Tanaka
Genshin
G
Mouri
Takanori
T
Sano
Colm
C
O'Tuathaigh
John L
JL
Waddington
Suzanne
S
Prenter
Norman
N
Delanty
Michael A
MA
Farrell
Donncha F
DF
O'Brien
Ronán M
RM
Conroy
Raymond L
RL
Stallings
Javier
J
DeFelipe
David C
DC
Henshall
D000328:Adult; D000818:Animals; D056654:CA3 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D049229:Dendritic Spines / Q000187:drug effects / Q000473:pathology; D004833:Epilepsy, Temporal Lobe / Q000235:genetics / Q000473:pathology; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism*; D017966:Pyramidal Cells / Q000187:drug effects / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D012008:Recurrence; D012640:Seizures / Q000235:genetics* / Q000517:prevention & control*; D013226:Status Epilepticus / Q000235:genetics / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
C569273:MIRN134 microRNA, human; D035683:MicroRNAs; C551912:Mirn134 microRNA, mouse; D018696:Neuroprotective Agents; D007608:Kainic Acid