title: Aberrant expression of miR-218 and miR-204 in human mesial temporal lobe epilepsy and hippocampal sclerosis-convergence on axonal guidance.
abstract: OBJECTIVE
  Mesial temporal lobe epilepsy (MTLE) is one of the most common types of the intractable epilepsies and is most often associated with hippocampal sclerosis (HS), which is characterized by pronounced loss of hippocampal pyramidal neurons. microRNAs (miRNAs) have been shown to be dysregulated in epilepsy and neurodegenerative diseases, and we hypothesized that miRNAs could be involved in the pathogenesis of MTLE and HS.
  
  
  METHODS
  miRNA expression was quantified in hippocampal specimens from human patients using miRNA microarray and quantitative real-time polymerase chain reaction RT-PCR, and by RNA-seq on fetal brain specimens from domestic pigs. In situ hybridization was used to show the spatial distribution of miRNAs in the human hippocampus. The potential effect of miRNAs on targets genes was investigated using the dual luciferase reporter gene assay.
  
  
  RESULTS
  miRNA expression profiling showed that 25 miRNAs were up-regulated and 5 were down-regulated in hippocampus biopsies of MTLE/HS patients compared to controls. We showed that miR-204 and miR-218 were significantly down-regulated in MTLE and HS, and both were expressed in neurons in all subfields of normal hippocampus. Moreover, miR-204 and miR-218 showed strong changes in expression during fetal development of the hippocampus in pigs, and we identified four target genes, involved in axonal guidance and synaptic plasticity, ROBO1, GRM1, SLC1A2, and GNAI2, as bona fide targets of miR-218. GRM1 was also shown to be a direct target of miR-204.
  
  
  CONCLUSIONS
  miR-204 and miR-218 are developmentally regulated in the hippocampus and may contribute to the molecular mechanisms underlying the pathogenesis of MTLE and HS.
authors.affiliation: Department of Cellular and Molecular Medicine, Wilhelm Johannsen Center for Functional Genome Research, University of Copenhagen, Copenhagen, Denmark; Research Laboratory for Stereology and Neuroscience, Bispebjerg Hospital, Copenhagen, Denmark.
authors.forename: Sanne S
authors.initials: SS
authors.lastname: Kaalund
authors.forename: Morten T
authors.initials: MT
authors.lastname: Venø
authors.forename: Mads
authors.initials: M
authors.lastname: Bak
authors.forename: Rikke S
authors.initials: RS
authors.lastname: Møller
authors.forename: Henning
authors.initials: H
authors.lastname: Laursen
authors.forename: Flemming
authors.initials: F
authors.lastname: Madsen
authors.forename: Helle
authors.initials: H
authors.lastname: Broholm
authors.forename: Bjørn
authors.initials: B
authors.lastname: Quistorff
authors.forename: Peter
authors.initials: P
authors.lastname: Uldall
authors.forename: Niels
authors.initials: N
authors.lastname: Tommerup
authors.forename: Sakari
authors.initials: S
authors.lastname: Kauppinen
authors.forename: Anne
authors.initials: A
authors.lastname: Sabers
authors.forename: Kees
authors.initials: K
authors.lastname: Fluiter
authors.forename: Lisbeth B
authors.initials: LB
authors.lastname: Møller
authors.forename: Anne Y
authors.initials: AY
authors.lastname: Nossent
authors.forename: Asli
authors.initials: A
authors.lastname: Silahtaroglu
authors.forename: Jørgen
authors.initials: J
authors.lastname: Kjems
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aronica
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Tümer
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D015331:Cohort Studies; D003718:Denmark; D004622:Embryo, Mammalian; D004833:Epilepsy, Temporal Lobe / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D027342:Excitatory Amino Acid Transporter 2; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology*; D050491:Glutamate Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009426:Netherlands; D017966:Pyramidal Cells / Q000378:metabolism / Q000473:pathology; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D015203:Reproducibility of Results; D012598:Sclerosis / Q000209:etiology / Q000473:pathology; D017423:Sequence Analysis, RNA; D013552:Swine; D055815:Young Adult
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D050491:Glutamate Plasma Membrane Transport Proteins; C549404:MIRN204 microRNA, human; C547471:MIRN218 microRNA, human; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D018094:Receptors, Metabotropic Glutamate; C493397:SLC1A2 protein, human
keywords: Epilepsy; Hippocampus; ROBO1; miR-218