title: MicroRNA 101b Is Downregulated in the Prefrontal Cortex of a Genetic Model of Depression and Targets the Glutamate Transporter SLC1A1 (EAAT3) in Vitro.
abstract: MicroRNAs (miRNAs) are small regulatory molecules that cause translational repression by base pairing with target mRNAs. Cumulative evidence suggests that changes in miRNA expression may in part underlie the pathophysiology and treatment of neuropsychiatric disorders, including major depressive disorder (MDD).
  
  
  
  A miRNA expression assay that can simultaneously detect 423 rat miRNAs (miRBase v.17) was used to profile the prefrontal cortex (PFC) of a genetic rat model of MDD (the Flinders Sensitive Line [FSL]) and the controls, the Flinders Resistant Line (FRL). Gene expression data from the PFC of FSL/FRL animals (GEO accession no. GSE20388) were used to guide mRNA target selection. Luciferase reporter assays were used to verify miRNA targets in vitro.
  
  
  
  We identified 23 miRNAs that were downregulated in the PFC of the FSL model compared with controls. Interestingly, one of the identified miRNAs (miR-101b) is highly conserved between rat and human and was recently found to be downregulated in the PFC of depressed suicide subjects. Using a combination of in silico and in vitro analyses, we found that miR-101b targets the neuronal glutamate transporter SLC1A1 (also known as EAAC1 or EAAT3). Accordingly, both mRNA and protein levels of SLC1A1 were found to be upregulated in the PFC of the FSL model.
  
  
  
  Besides providing a list of novel miRNAs associated with depression-like states, this preclinical study replicated the human association of miR-101 with depression. In addition, since one of the targets of miR-101b appears to be a glutamate transporter, our preclinical data support the hypothesis of a glutamatergic dysregulation being implicated in the etiology of depression.
authors: Department of Molecular Medicine and Surgery, Neurogenetics Unit (Drs Wei, Melas, Liu, and Lavebratt), Center for Molecular Medicine (Drs Wei, Melas, Villaescusa, Liu, Xu, and Lavebratt), Department of Clinical Neuroscience (Drs Melas and Mathé), Department of Molecular Biochemistry and Biophysics, Neurogenetics Unit (Dr Villaescusa), and Department of Medicine (Dr Xu), Karolinska Institutet, Stockholm, Sweden; Department of Neuroscience and Pharmacology, Laboratory for Neural Plasticity, University of Copenhagen, Denmark (Drs Christiansen, Elbrønd-Bek, and Woldbye); Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark (Dr Wegener); Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa (Dr Wegener). yabin.wei@ki.se.
authors: Ya Bin
authors: YB
authors: Wei
authors: Department of Molecular Medicine and Surgery, Neurogenetics Unit (Drs Wei, Melas, Liu, and Lavebratt), Center for Molecular Medicine (Drs Wei, Melas, Villaescusa, Liu, Xu, and Lavebratt), Department of Clinical Neuroscience (Drs Melas and Mathé), Department of Molecular Biochemistry and Biophysics, Neurogenetics Unit (Dr Villaescusa), and Department of Medicine (Dr Xu), Karolinska Institutet, Stockholm, Sweden; Department of Neuroscience and Pharmacology, Laboratory for Neural Plasticity, University of Copenhagen, Denmark (Drs Christiansen, Elbrønd-Bek, and Woldbye); Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark (Dr Wegener); Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa (Dr Wegener).
authors: Philippe A
authors: PA
authors: Melas
authors: Department of Molecular Medicine and Surgery, Neurogenetics Unit (Drs Wei, Melas, Liu, and Lavebratt), Center for Molecular Medicine (Drs Wei, Melas, Villaescusa, Liu, Xu, and Lavebratt), Department of Clinical Neuroscience (Drs Melas and Mathé), Department of Molecular Biochemistry and Biophysics, Neurogenetics Unit (Dr Villaescusa), and Department of Medicine (Dr Xu), Karolinska Institutet, Stockholm, Sweden; Department of Neuroscience and Pharmacology, Laboratory for Neural Plasticity, University of Copenhagen, Denmark (Drs Christiansen, Elbrønd-Bek, and Woldbye); Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark (Dr Wegener); Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa (Dr Wegener).
authors: J Carlos
authors: JC
authors: Villaescusa
authors: Department of Molecular Medicine and Surgery, Neurogenetics Unit (Drs Wei, Melas, Liu, and Lavebratt), Center for Molecular Medicine (Drs Wei, Melas, Villaescusa, Liu, Xu, and Lavebratt), Department of Clinical Neuroscience (Drs Melas and Mathé), Department of Molecular Biochemistry and Biophysics, Neurogenetics Unit (Dr Villaescusa), and Department of Medicine (Dr Xu), Karolinska Institutet, Stockholm, Sweden; Department of Neuroscience and Pharmacology, Laboratory for Neural Plasticity, University of Copenhagen, Denmark (Drs Christiansen, Elbrønd-Bek, and Woldbye); Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark (Dr Wegener); Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa (Dr Wegener).
authors: Jia Jia
authors: JJ
authors: Liu
authors: Department of Molecular Medicine and Surgery, Neurogenetics Unit (Drs Wei, Melas, Liu, and Lavebratt), Center for Molecular Medicine (Drs Wei, Melas, Villaescusa, Liu, Xu, and Lavebratt), Department of Clinical Neuroscience (Drs Melas and Mathé), Department of Molecular Biochemistry and Biophysics, Neurogenetics Unit (Dr Villaescusa), and Department of Medicine (Dr Xu), Karolinska Institutet, Stockholm, Sweden; Department of Neuroscience and Pharmacology, Laboratory for Neural Plasticity, University of Copenhagen, Denmark (Drs Christiansen, Elbrønd-Bek, and Woldbye); Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark (Dr Wegener); Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa (Dr Wegener).
authors: Ning
authors: N
authors: Xu
authors: Department of Molecular Medicine and Surgery, Neurogenetics Unit (Drs Wei, Melas, Liu, and Lavebratt), Center for Molecular Medicine (Drs Wei, Melas, Villaescusa, Liu, Xu, and Lavebratt), Department of Clinical Neuroscience (Drs Melas and Mathé), Department of Molecular Biochemistry and Biophysics, Neurogenetics Unit (Dr Villaescusa), and Department of Medicine (Dr Xu), Karolinska Institutet, Stockholm, Sweden; Department of Neuroscience and Pharmacology, Laboratory for Neural Plasticity, University of Copenhagen, Denmark (Drs Christiansen, Elbrønd-Bek, and Woldbye); Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark (Dr Wegener); Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa (Dr Wegener).
authors: Søren Hofman
authors: SH
authors: Christiansen
authors: Department of Molecular Medicine and Surgery, Neurogenetics Unit (Drs Wei, Melas, Liu, and Lavebratt), Center for Molecular Medicine (Drs Wei, Melas, Villaescusa, Liu, Xu, and Lavebratt), Department of Clinical Neuroscience (Drs Melas and Mathé), Department of Molecular Biochemistry and Biophysics, Neurogenetics Unit (Dr Villaescusa), and Department of Medicine (Dr Xu), Karolinska Institutet, Stockholm, Sweden; Department of Neuroscience and Pharmacology, Laboratory for Neural Plasticity, University of Copenhagen, Denmark (Drs Christiansen, Elbrønd-Bek, and Woldbye); Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark (Dr Wegener); Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa (Dr Wegener).
authors: Heidi
authors: H
authors: Elbrønd-Bek
authors: Department of Molecular Medicine and Surgery, Neurogenetics Unit (Drs Wei, Melas, Liu, and Lavebratt), Center for Molecular Medicine (Drs Wei, Melas, Villaescusa, Liu, Xu, and Lavebratt), Department of Clinical Neuroscience (Drs Melas and Mathé), Department of Molecular Biochemistry and Biophysics, Neurogenetics Unit (Dr Villaescusa), and Department of Medicine (Dr Xu), Karolinska Institutet, Stockholm, Sweden; Department of Neuroscience and Pharmacology, Laboratory for Neural Plasticity, University of Copenhagen, Denmark (Drs Christiansen, Elbrønd-Bek, and Woldbye); Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark (Dr Wegener); Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa (Dr Wegener).
authors: David Paul Drucker
authors: DP
authors: Woldbye
authors: Department of Molecular Medicine and Surgery, Neurogenetics Unit (Drs Wei, Melas, Liu, and Lavebratt), Center for Molecular Medicine (Drs Wei, Melas, Villaescusa, Liu, Xu, and Lavebratt), Department of Clinical Neuroscience (Drs Melas and Mathé), Department of Molecular Biochemistry and Biophysics, Neurogenetics Unit (Dr Villaescusa), and Department of Medicine (Dr Xu), Karolinska Institutet, Stockholm, Sweden; Department of Neuroscience and Pharmacology, Laboratory for Neural Plasticity, University of Copenhagen, Denmark (Drs Christiansen, Elbrønd-Bek, and Woldbye); Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark (Dr Wegener); Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa (Dr Wegener).
authors: Gregers
authors: G
authors: Wegener
authors: Department of Molecular Medicine and Surgery, Neurogenetics Unit (Drs Wei, Melas, Liu, and Lavebratt), Center for Molecular Medicine (Drs Wei, Melas, Villaescusa, Liu, Xu, and Lavebratt), Department of Clinical Neuroscience (Drs Melas and Mathé), Department of Molecular Biochemistry and Biophysics, Neurogenetics Unit (Dr Villaescusa), and Department of Medicine (Dr Xu), Karolinska Institutet, Stockholm, Sweden; Department of Neuroscience and Pharmacology, Laboratory for Neural Plasticity, University of Copenhagen, Denmark (Drs Christiansen, Elbrønd-Bek, and Woldbye); Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark (Dr Wegener); Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa (Dr Wegener).
authors: Aleksander A
authors: AA
authors: Mathé
authors: Department of Molecular Medicine and Surgery, Neurogenetics Unit (Drs Wei, Melas, Liu, and Lavebratt), Center for Molecular Medicine (Drs Wei, Melas, Villaescusa, Liu, Xu, and Lavebratt), Department of Clinical Neuroscience (Drs Melas and Mathé), Department of Molecular Biochemistry and Biophysics, Neurogenetics Unit (Dr Villaescusa), and Department of Medicine (Dr Xu), Karolinska Institutet, Stockholm, Sweden; Department of Neuroscience and Pharmacology, Laboratory for Neural Plasticity, University of Copenhagen, Denmark (Drs Christiansen, Elbrønd-Bek, and Woldbye); Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark (Dr Wegener); Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa (Dr Wegener).
authors: Catharina
authors: C
authors: Lavebratt
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D003865:Major Depressive Disorder / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D004195:Disease Models, Animal; D015536:Down-Regulation; D050580:Excitatory Amino Acid Transporter 3 / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011919:Rats, Inbred Strains; D015398:Signal Transduction
chemical_list: D050580:Excitatory Amino Acid Transporter 3; C579142:MIRN101 microRNA, rat; D035683:MicroRNAs; D012333:RNA, Messenger; C493398:Slc1a1 protein, rat; D018698:Glutamic Acid
keywords: DCBXA; EAAC1; depression; epigenetics; miRNA