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

Billy Vuong,Tiina M Kauppinen,Stephanie Rozbacher,Stephanie M Kereliuk,Gary Odero,Troy J Pereira,Vernon W Dolinsky,Mackenzie Stevenson

doi:10.1186/s12974-017-0859-9

Abstract

BackgroundBirth 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.MethodsIn 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.ResultsIn 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.ConclusionsThese 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.

Highlights

Birth cohort studies link gestational diabetes mellitus (GDM) with impaired cognitive performance in the offspring
Gestational diabetes mellitus and/or postnatal high-fat and sucrose diet induce atypical inattentive behavior and recognition memory impairment in offspring Offspring of GDM dams were analyzed at 14–15 weeks of age, which is equivalent to the young adult stage in humans
Rodents typically avoid being exposed to open space but prefer to remain close to the walls as a thigmotactic response [38] and actively observe their surroundings by rearing, suggesting that the GDM-high-fat and sucrose (HFS) offspring show reduced anxiety level and inattentive behavior as they explore the center of the open field (OF) while not actively surveying their surroundings as indicated by their reduced rearing

Summary

Introduction

Birth cohort studies link gestational diabetes mellitus (GDM) with impaired cognitive performance in the offspring. 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. The combination of human cohort studies and research using rodent models with controlled pre- and postnatal conditions has demonstrated that diabetes during pregnancy during critical stages of development affects health outcomes in the offspring [2]. Several human cohort studies have linked diabetes during pregnancy with impaired cognitive abilities [3,4,5,6] and psychiatric disorders [7, 8] in the offspring. The mechanisms that link GDM to the development of cognitive impairments in the offspring remain to be elucidated

Methods

Results

Discussion

Conclusion