Exposure to gestational diabetes mellitus induces neuroinflammation, derangement of hippocampal neurons, and cognitive changes in rat offspring
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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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Offspring from the gestational diabetes mellitus model exhibit a hyperactive immune response that manifests in neuroinflammation, which was correlated with cognitive impairment and reduced synaptic integrity.
“Further studies using this GDM model have demonstrated that the offspring exhibit a hyperactive immune response [108] that manifests in neuroinflammation, which was correlated with cognitive impairment and reduced synaptic integrity [109].”
From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [109]
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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)
- PMC
- PMC5384149
- 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
- gold
- doi.org
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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