Cited by 147Gestational Diabetes Research and ManagementNeuroinflammation and Neurodegeneration MechanismsBirth, Development, and Health

Exposure to gestational diabetes mellitus induces neuroinflammation, derangement of hippocampal neurons, and cognitive changes in rat offspring

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Vuong, Billy, Odero, Gary, Rozbacher, Stephanie, Stevenson, Mackenzie, Kereliuk, Stephanie M., Pereira, Troy J., Dolinsky, Vernon W., Kauppinen, Tiina M.·2017·Journal of Neuroinflammation

Abstract

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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Authors
Vuong, B., Odero, G., Rozbacher, S., Stevenson, M., Kereliuk, S. M., Pereira, T. J., Dolinsky, V. W., & Kauppinen, T. M.
Affiliations
  • Health Sciences Centre (CA)
  • Children's Hospital Research Institute of Manitoba (CA)
Corresponding author
Kauppinen, Tiina M.
Venue
Journal of Neuroinflammation
Published
2017-04-07
Volume
14
Issue
1
Pages
80-80
ISSN
1742-2094 (ISSN-L)
OpenAlex
W2604467698
Cited by
147
References
70
Citations by year
2026: 11 · 2025: 19 · 2024: 13 · 2023: 25 · 2022: 22 · 2021: 17 · 2020: 17 · 2019: 11 · 2018: 9 · 2017: 2 · 2016: 1
FWCI
12.55
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Journal of Neuroinflammation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Mspace (University of Manitoba) (submittedVersion)
Funders
  • Manitoba Health Research Council
  • Children's Hospital Foundation Winnipeg, Manitoba
  • Health Sciences Centre Foundation Winnipeg
  • Canadian Institutes of Health Research (MOP136885)
  • Research Manitoba
Topics
  • Health Sciences › Medicine › Obstetrics and Gynecology › Gestational Diabetes Research and Management
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
Keywords
gestational diabetes mellitus, neuroinflammation, hippocampus, cognitive impairment, microglial activation, CX3CR1, synaptic pruning, reactive gliosis, recognition memory, inattentive behavior, high-fat high-sugar diet, palmitate, nitric oxide, superoxide, inflammatory cytokines, cornu ammonis 1, synaptic integrity
MeSH terms
Animals, Cells, Cultured, Cognition, Female, Hippocampus, Inflammation, Male, Neurons, Pregnancy, Prenatal Exposure Delayed Effects, Random Allocation, Diabetes, Gestational, Rats, Sprague-Dawley, Inflammation Mediators, Dietary Sucrose, Rats, Diet, High-Fat

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