title: Antidepressant-dependent mRNA changes in mouse associated with hippocampal neurogenesis in a mouse model of depression.
abstract: BACKGROUND
  Monoaminergic imbalances play a role in the pathogenesis of depression and most common antidepressant drugs act on monoamine neurotransmitters. However, the lag time between restoring neurochemical balance and symptom improvement suggests that the response to drugs involves complex biological events downstream of primary targets that have not yet been fully characterized. Here, we report a mouse mRNA expression study to evaluate the effect of escitalopram (a serotonergic antidepressant) and nortriptyline (a noradrenergic antidepressant) on genes that are involved in the pathogenesis of depression and to assess the similarities and differences between two drugs on gene expression levels.
  
  
  METHODS
  Genome-wide RNA expression data from the hippocampal tissues of four inbred mouse strains (129S1/SvlmJ, C57LB/6J, DBA/2J and FVB/NJ) were treated with varying doses of either nortriptyline (NRI) or escitalopram (SSRI) and subjected to two different depressogenic protocols. Following robust multichip average normalization, we applied the nonparametric RankProd approach to identify differentially expressed genes in response to drugs across the four strains. Pathway analysis was subsequently carried out on top-ranking genes to gain further biological insights.
  
  
  RESULTS
  A total of 371 genes were significantly differentially expressed in response to nortriptyline, whereas 383 were altered by escitalopram. Genes involved in the pathways of integrin signalling (Fnlb, Mapk1, Mapk8), synaptic transmission (Cacnb1, Dnajc5, Kcnma1, Slc1a2) or Huntington disease (Crebbp, Dlg4, Ncor1) were altered by both nortriptyline and escitalopram. Several biological processes and pathways were identified, which could explain the divergence between the molecular mechanisms of nortriptyline and escitalopram.
  
  
  CONCLUSIONS
  From a large-scale animal study, we obtain gene sets comprised of commonly and differentially expressed genes in response to different antidepressant drug treatments. The results may help to characterize the response to antidepressant treatment, shed further light on the neurobiology of depressive disorders and inform future animal and human studies. Finally, the top-ranking pathways from Ingenuity provide further evidence for the hippocampal neurogenesis hypothesis of major depressive disorders.
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, King's College London, London, UK. karim.malki@iop.kcl.ac.uk
authors.forename: Karim
authors.initials: K
authors.lastname: Malki
authors.forename: Anbarasu
authors.initials: A
authors.lastname: Lourdusamy
authors.forename: Elke
authors.initials: E
authors.lastname: Binder
authors.forename: Jose
authors.initials: J
authors.lastname: Payá-Cano
authors.forename: Frans
authors.initials: F
authors.lastname: Sluyter
authors.forename: Ian
authors.initials: I
authors.lastname: Craig
authors.forename: Robert
authors.initials: R
authors.lastname: Keers
authors.forename: Peter
authors.initials: P
authors.lastname: McGuffin
authors.forename: Rudolf
authors.initials: R
authors.lastname: Uher
authors.forename: Leonard C
authors.initials: LC
authors.lastname: Schalkwyk
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015283:Citalopram / Q000494:pharmacology* / Q000627:therapeutic use; D003863:Depression / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D055495:Neurogenesis / Q000187:drug effects; D009661:Nortriptyline / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism*
chemical_list: D000928:Antidepressive Agents; D012333:RNA, Messenger; D015283:Citalopram; D009661:Nortriptyline