title: Estrogen receptor alpha deficiency protects against development of cognitive impairment in murine lupus.
abstract: BACKGROUND
  One of the more profound features of systemic lupus erythematosus (SLE) is that females have a 9:1 prevalence of this disease over males. Up to 80% of SLE patients have cognitive defects or affective disorders. The mechanism of CNS injury responsible for cognitive impairment is unknown. We previously showed that ERα deficiency significantly reduced renal disease and increased survival in lupus-prone mice. We hypothesized that ERα deficiency would be similarly protective in the brain, and that ERα may play a role in modulating blood-brain barrier (BBB) integrity and/or neuroinflammation in lupus-prone mice.
  
  
  METHODS
  MRL/lpr ERα+/+ and ERαKO mice (n = 46) were ovariectomized, received 17β-estradiol pellets, and underwent radial arm water maze (WRAM) and novel object recognition (NOR) testing starting at eight weeks of age. Mice were sacrificed and brains were hemisected and processed for either immunohistochemistry, or hippocampus and parietal cortex dissection for Western blotting.
  
  
  RESULTS
  MRL/lpr ERαKO mice (n = 21) performed significantly better in WRAM testing than wild-type MRL/lpr mice (n = 25). There was a significant reduction in reference memory errors (P <0.007), working memory errors (P <0.05), and start arm errors (P <0.02) in ERαKO mice. There were significant differences in NOR testing, particularly total exploration time, with ERα deficiency normalizing behavior. No significant differences were seen in markers of tight junction, astrogliosis, or microgliosis in the hippocampus or cortex by Western blot, however, there was a significant reduction in numbers of Iba1+ activated microglia in the hippocampus of ERαKO mice, as evidenced by immunohistochemietry (IHC).
  
  
  CONCLUSIONS
  ERα deficiency provides significant protection against cognitive deficits in MRL/lpr mice as early as eight weeks of age. Additionally, the significant reduction in Iba1+ activated microglia in the MRL/lpr ERαKO mice was consistent with reduced inflammation, and may represent a biological mechanism for the cognitive improvement observed.
authors.affiliation: Division of Rheumatology and Immunology, Department of Neurosciences, and Ralph H Johnson Veterans Affairs Hospital, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 814, MSC637, Charleston, SC, 29425, USA. cunnima@musc.edu.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Cunningham
authors.affiliation: Division of Rheumatology and Immunology, Department of Neurosciences, and Ralph H Johnson Veterans Affairs Hospital, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 814, MSC637, Charleston, SC, 29425, USA. wirthj@musc.edu.
authors.forename: Jena R
authors.initials: JR
authors.lastname: Wirth
authors.affiliation: Division of Rheumatology and Immunology, Department of Neurosciences, and Ralph H Johnson Veterans Affairs Hospital, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 814, MSC637, Charleston, SC, 29425, USA. freemal@musc.edu.
authors.forename: Linnea R
authors.initials: LR
authors.lastname: Freeman
authors.affiliation: Division of Rheumatology and Immunology, Department of Neurosciences, and Ralph H Johnson Veterans Affairs Hospital, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 814, MSC637, Charleston, SC, 29425, USA. boger@musc.edu.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Boger
authors.affiliation: Division of Rheumatology and Immunology, Department of Neurosciences, and Ralph H Johnson Veterans Affairs Hospital, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 814, MSC637, Charleston, SC, 29425, USA. granholm@musc.edu.
authors.forename: Ann-Charlotte
authors.initials: AC
authors.lastname: Granholm
authors.affiliation: Division of Rheumatology and Immunology, Department of Neurosciences, and Ralph H Johnson Veterans Affairs Hospital, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 814, MSC637, Charleston, SC, 29425, USA. gilkeson@musc.edu.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Gilkeson
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000378:metabolism* / Q000517:prevention & control*; D047628:Estrogen Receptor alpha / Q000172:deficiency*; D005260:Female; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism* / Q000517:prevention & control*; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D047628:Estrogen Receptor alpha