title: Hippocampal demyelination and memory dysfunction are associated with increased levels of the neuronal microRNA miR-124 and reduced AMPA receptors.
abstract: OBJECTIVE
  Hippocampal demyelination, a common feature of postmortem multiple sclerosis (MS) brains, reduces neuronal gene expression and is a likely contributor to the memory impairment that is found in >40% of individuals with MS. How demyelination alters neuronal gene expression is unknown.
  
  
  METHODS
  To explore whether loss of hippocampal myelin alters expression of neuronal microRNAs (miRNAs), we compared miRNA profiles from myelinated and demyelinated hippocampi from postmortem MS brains and performed validation studies.
  
  
  RESULTS
  A network-based interaction analysis depicts a correlation between increased neuronal miRNAs and decreased neuronal genes identified in our previous study. The neuronal miRNA miR-124 was increased in demyelinated MS hippocampi and targets mRNAs encoding 26 neuronal proteins that were decreased in demyelinated hippocampus, including the ionotrophic glutamate receptors AMPA2 and AMPA3. Hippocampal demyelination in mice also increased miR-124, reduced expression of AMPA receptors, and decreased memory performance in water maze tests. Remyelination of the mouse hippocampus reversed these changes.
  
  
  CONCLUSIONS
  We establish here that myelin alters neuronal gene expression and function by modulating the levels of the neuronal miRNA miR-124. Inhibition of miR-124 in hippocampal neurons may provide a therapeutic approach to improve memory performance in MS patients.
authors.affiliation: Department of Neurosciences, Cleveland Clinic, Cleveland, OH 44195, USA. duttar@ccf.org
authors.forename: Ranjan
authors.initials: R
authors.lastname: Dutta
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Chomyk
authors.forename: Ansi
authors.initials: A
authors.lastname: Chang
authors.forename: Michael V
authors.initials: MV
authors.lastname: Ribaudo
authors.forename: Sadie A
authors.initials: SA
authors.lastname: Deckard
authors.forename: Mary K
authors.initials: MK
authors.lastname: Doud
authors.forename: Dale D
authors.initials: DD
authors.lastname: Edberg
authors.forename: Brian
authors.initials: B
authors.lastname: Bai
authors.forename: Michael
authors.initials: M
authors.lastname: Li
authors.forename: Sergio E
authors.initials: SE
authors.lastname: Baranzini
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fox
authors.forename: Susan M
authors.initials: SM
authors.lastname: Staugaitis
authors.forename: Wendy B
authors.initials: WB
authors.lastname: Macklin
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Trapp
mesh_terms: D000818:Animals; D003471:Cuprizone / Q000633:toxicity; D003711:Demyelinating Diseases / Q000209:etiology / Q000473:pathology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000633:toxicity; D008569:Memory Disorders / Q000209:etiology / Q000473:pathology*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000633:toxicity; D009103:Multiple Sclerosis / Q000139:chemically induced / Q000150:complications / Q000473:pathology; D009474:Neurons / Q000378:metabolism*; D011180:Postmortem Changes; D012333:RNA, Messenger / Q000378:metabolism; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D020123:Sirolimus / Q000633:toxicity
chemical_list: D007166:Immunosuppressive Agents; C509207:MIRN124 microRNA, human; D035683:MicroRNAs; D008996:Monoamine Oxidase Inhibitors; D012333:RNA, Messenger; D018091:Receptors, AMPA; D003471:Cuprizone; D020123:Sirolimus