title: Telomerase dysregulation in the hippocampus of a rat model of depression: normalization by lithium.
abstract: BACKGROUND
  Telomeres are protective DNA-protein complexes at the ends of each chromosome, maintained primarily by the enzyme telomerase. Shortening of the blood leukocyte telomeres is associated with aging, several chronic diseases, and stress, eg, major depression. Hippocampus is pivotal in the regulation of cognition and mood and the main brain region of telomerase activity. Whether there is telomere dysfunction in the hippocampus of depressed subjects is unknown. Lithium, used in the treatment and relapse prevention of mood disorders, was found to protect against leukocyte telomere shortening in humans, but the mechanism has not been elucidated. To answer the questions whether telomeres are shortened and the telomerase activity changed in the hippocampus and whether lithium could reverse the process, we used a genetic model of depression, the Flinders Sensitive Line rat, and treated the animals with lithium.
  
  
  METHODS
  Telomere length, telomerase reverse transcriptase (Tert) expression, telomerase activity, and putative mediators of telomerase activity were investigated in the hippocampus of these animals.
  
  
  RESULTS
  The naïve Flinders Sensitive Line had shorter telomere length, downregulated Tert expression, reduced brain-derived neurotrophic factor levels, and reduced telomerase activity compared with the Flinders Resistant Line controls. Lithium treatment normalized the Tert expression and telomerase activity in the Flinders Sensitive Line and upregulated β-catenin.
  
  
  CONCLUSIONS
  This is the first report showing telomere dysregulation in hippocampus of a well-defined depression model and restorative effects of lithium treatment. If replicated in other models of mood disorder, the findings will contribute to understanding both the telomere function and the mechanism of lithium action in hippocampus of depressed patients.
authors.affiliation: Department of Molecular Medicine and Surgery, Neurogenetics Unit, Karolinska Institutet, Stockholm, Sweden (Mr Wei, Drs Backlund and Lavebratt); Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden (Mr Wei, Dr Lavebratt); Centre for Psychiatric Research and Education, Karolinska Institutet, Clinic for Affective Disorders, Stockholm, Sweden (Drs Backlund and Mathé); 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); and Department of Clinical Neuroscience, Section for Psychiatry, Karolinska Institutet, Stockholm, Sweden (Dr Mathé).
authors.forename: Ya Bin
authors.initials: YB
authors.lastname: Wei
authors.affiliation: Department of Molecular Medicine and Surgery, Neurogenetics Unit, Karolinska Institutet, Stockholm, Sweden (Mr Wei, Drs Backlund and Lavebratt); Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden (Mr Wei, Dr Lavebratt); Centre for Psychiatric Research and Education, Karolinska Institutet, Clinic for Affective Disorders, Stockholm, Sweden (Drs Backlund and Mathé); 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); and Department of Clinical Neuroscience, Section for Psychiatry, Karolinska Institutet, Stockholm, Sweden (Dr Mathé).
authors.forename: Lena
authors.initials: L
authors.lastname: Backlund
authors.affiliation: Department of Molecular Medicine and Surgery, Neurogenetics Unit, Karolinska Institutet, Stockholm, Sweden (Mr Wei, Drs Backlund and Lavebratt); Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden (Mr Wei, Dr Lavebratt); Centre for Psychiatric Research and Education, Karolinska Institutet, Clinic for Affective Disorders, Stockholm, Sweden (Drs Backlund and Mathé); 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); and Department of Clinical Neuroscience, Section for Psychiatry, Karolinska Institutet, Stockholm, Sweden (Dr Mathé).
authors.forename: Gregers
authors.initials: G
authors.lastname: Wegener
authors.affiliation: Department of Molecular Medicine and Surgery, Neurogenetics Unit, Karolinska Institutet, Stockholm, Sweden (Mr Wei, Drs Backlund and Lavebratt); Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden (Mr Wei, Dr Lavebratt); Centre for Psychiatric Research and Education, Karolinska Institutet, Clinic for Affective Disorders, Stockholm, Sweden (Drs Backlund and Mathé); 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); and Department of Clinical Neuroscience, Section for Psychiatry, Karolinska Institutet, Stockholm, Sweden (Dr Mathé).
authors.forename: Aleksander A
authors.initials: AA
authors.lastname: Mathé
authors.affiliation: Department of Molecular Medicine and Surgery, Neurogenetics Unit, Karolinska Institutet, Stockholm, Sweden (Mr Wei, Drs Backlund and Lavebratt); Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden (Mr Wei, Dr Lavebratt); Centre for Psychiatric Research and Education, Karolinska Institutet, Clinic for Affective Disorders, Stockholm, Sweden (Drs Backlund and Mathé); 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); and Department of Clinical Neuroscience, Section for Psychiatry, Karolinska Institutet, Stockholm, Sweden (Dr Mathé).
authors.forename: Catharina
authors.initials: C
authors.lastname: Lavebratt
mesh_terms: D000375:Aging / Q000187:drug effects* / Q000378:metabolism / Q000523:psychology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003863:Depression / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D018020:Lithium Compounds / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D019098:Telomerase / Q000378:metabolism*; D016615:Telomere / Q000187:drug effects / Q000378:metabolism*; D016896:Treatment Outcome; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D018020:Lithium Compounds; D051176:beta Catenin; D019098:Telomerase
keywords: animal model; depression; hippocampus; lithium; telomerase; telomere