title: Exposure to gestational diabetes mellitus induces neuroinflammation, derangement of hippocampal neurons, and cognitive changes in rat offspring.
abstract: Birth cohort studies link gestational diabetes mellitus (GDM) with impaired cognitive performance in the offspring. However, the mechanisms involved are unknown. We tested the hypothesis that obesity-associated GDM induces chronic neuroinflammation and disturbs the development of neuronal circuitry resulting in impaired cognitive abilities in the offspring.
  
  
  
  In rats, GDM was induced by feeding dams a diet high in sucrose and fatty acids. Brains of neonatal (E20) and young adult (15-week-old) offspring of GDM and lean dams were analyzed by immunohistochemistry, cytokine assay, and western blotting. Young adult offspring of GDM and lean dams went also through cognitive assessment. Cultured microglial responses to elevated glucose and/or fatty acids levels were analyzed.
  
  
  
  In rats, impaired recognition memory was observed in the offspring of GDM dams. GDM exposure combined with a postnatal high-fat and sucrose diet resulted in atypical inattentive behavior in the offspring. These cognitive changes correlated with reduced density and derangement of Cornu Ammonis 1 pyramidal neuronal layer, decreased hippocampal synaptic integrity, increased neuroinflammatory status, and reduced expression of CX3CR1, the microglial fractalkine receptor regulating microglial pro-inflammatory responses and synaptic pruning. Primary microglial cultures that were exposed to high concentrations of glucose and/or palmitate were transformed into an activated, amoeboid morphology with increased nitric oxide and superoxide production, and altered their cytokine release profile.
  
  
  
  These findings demonstrate that GDM stimulates microglial activation and chronic inflammatory responses in the brain of the offspring that persist into young adulthood. Reactive gliosis correlates positively with hippocampal synaptic decline and cognitive impairments. The elevated pro-inflammatory cytokine expression at the critical period of hippocampal synaptic maturation suggests that neuroinflammation might drive the synaptic and cognitive decline in the offspring of GDM dams. The importance of microglia in this process is supported by the reduced Cx3CR1 expression as an indication of the loss of microglial control of inflammatory responses and phagocytosis and synaptic pruning in GDM offspring.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Manitoba, 753 McDermot Avenue, Winnipeg, Manitoba, R3E 0T6, Canada.|Neuroscience Research Program, Kleysen Institute for Advanced Medicine, Health Sciences Center, SR434 - 710 William Avenue, Winnipeg, Manitoba, R3E 0Z3, Canada.
authors.forename: Billy
authors.initials: B
authors.lastname: Vuong
authors.affiliation: Department of Pharmacology and Therapeutics, University of Manitoba, 753 McDermot Avenue, Winnipeg, Manitoba, R3E 0T6, Canada.|Neuroscience Research Program, Kleysen Institute for Advanced Medicine, Health Sciences Center, SR434 - 710 William Avenue, Winnipeg, Manitoba, R3E 0Z3, Canada.
authors.forename: Gary
authors.initials: G
authors.lastname: Odero
authors.affiliation: Neuroscience Research Program, Kleysen Institute for Advanced Medicine, Health Sciences Center, SR434 - 710 William Avenue, Winnipeg, Manitoba, R3E 0Z3, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Rozbacher
authors.affiliation: Neuroscience Research Program, Kleysen Institute for Advanced Medicine, Health Sciences Center, SR434 - 710 William Avenue, Winnipeg, Manitoba, R3E 0Z3, Canada.
authors.forename: Mackenzie
authors.initials: M
authors.lastname: Stevenson
authors.affiliation: Department of Pharmacology and Therapeutics, University of Manitoba, 753 McDermot Avenue, Winnipeg, Manitoba, R3E 0T6, Canada.|The Children's Hospital Research Institute of Manitoba, 601 John Buhler Research Centre, 715 McDermott Avenue, Winnipeg, Manitoba, R3E 3P4, Canada.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Kereliuk
authors.affiliation: Department of Pharmacology and Therapeutics, University of Manitoba, 753 McDermot Avenue, Winnipeg, Manitoba, R3E 0T6, Canada.|The Children's Hospital Research Institute of Manitoba, 601 John Buhler Research Centre, 715 McDermott Avenue, Winnipeg, Manitoba, R3E 3P4, Canada.
authors.forename: Troy J
authors.initials: TJ
authors.lastname: Pereira
authors.affiliation: Department of Pharmacology and Therapeutics, University of Manitoba, 753 McDermot Avenue, Winnipeg, Manitoba, R3E 0T6, Canada.|The Children's Hospital Research Institute of Manitoba, 601 John Buhler Research Centre, 715 McDermott Avenue, Winnipeg, Manitoba, R3E 3P4, Canada.
authors.forename: Vernon W
authors.initials: VW
authors.lastname: Dolinsky
authors.affiliation: Department of Pharmacology and Therapeutics, University of Manitoba, 753 McDermot Avenue, Winnipeg, Manitoba, R3E 0T6, Canada. Tiina.Kauppinen@umanitoba.ca.|Neuroscience Research Program, Kleysen Institute for Advanced Medicine, Health Sciences Center, SR434 - 710 William Avenue, Winnipeg, Manitoba, R3E 0Z3, Canada. Tiina.Kauppinen@umanitoba.ca.|The Children's Hospital Research Institute of Manitoba, 601 John Buhler Research Centre, 715 McDermott Avenue, Winnipeg, Manitoba, R3E 3P4, Canada. Tiina.Kauppinen@umanitoba.ca.
authors.forename: Tiina M
authors.initials: TM
authors.lastname: Kauppinen
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003071:Cognition / Q000502:physiology*; D016640:Diabetes, Gestational / Q000378:metabolism* / Q000473:pathology; D059305:Diet, High-Fat / Q000009:adverse effects; D019422:Dietary Sucrose / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism* / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D019422:Dietary Sucrose; D018836:Inflammation Mediators
keywords: Gestational diabetes mellitus; Hippocampus; Microglia; Neurodevelopmental disorder; Neuroinflammation; Recognition memory; Synapse