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

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.

Neonatal overfeeding by small‐litter rearing sensitises hippocampal microglial responses to immune challenge: Reversal with neonatal repeated injections of saline or minocycline

“…This programming effect of early‐life diet on microglia extends beyond the hypothalamus; microglia are also increased in density in the hippocampus in adults that have been overfed as neonates . Similarly, recent studies have shown a primed hippocampal microglial profile in adult offspring from high‐saturated‐fat diet‐fed dams . Performance in hippocampally‐mediated learning tasks is less efficient in these rats and it appears that microglia in neonatally overfed rats are less responsive to a learning task compared to those in control‐fed rats .…”

“…16 Similarly, recent studies have shown a primed hippocampal microglial profile in adult offspring from high-saturated-fat diet-fed dams. 4,17 Performance in hippocampally-mediated learning tasks is less efficient in these rats 4,17 and it appears that microglia in neonatally overfed rats are less responsive to a learning task compared to those in control-fed rats. 16 Microglia have region-specific heterogeneity with different responses to stimuli in different brain regions.…”

Dietary Fructose Intake and Hippocampal Structure and Connectivity during Childhood

“…During adolescence, the hippocampus reaches peak volume, and begins to undergo synaptic pruning, eliminating unused connections [60,61], and prior studies have shown that the CA3 hippocampal subfield gradually begins to decrease in volume during mid childhood [61,62]. Work by Vuong et al found that synaptic pruning is delayed in juvenile rats exposed in utero to obese mothers with GDM [63]. In their findings, inflammation and recruitment of microglial cells occurred during post-natal development in the hippocampus, along with a reduction in synaptic pruning, and the animals presented with altered hippocampal morphology.…”

“…In their findings, inflammation and recruitment of microglial cells occurred during post-natal development in the hippocampus, along with a reduction in synaptic pruning, and the animals presented with altered hippocampal morphology. These findings suggest that prenatal environmental insults can result in hippocampal inflammation, reductions in synaptic pruning and altered hippocampal development [63]. Interestingly, Hershey et al, found that children with Type 1 diabetes had increased hippocampal volume, despite the commonly reported decreased volume in adults with Type 1 and Type 2 diabetes [64].…”

Intergenerational neurocognitive effects of intrauterine hyperglycemia on male offspring

“…Experimental investigations in animals indicated that uncontrolled diabetes mellitus was associated with morphological and functional alterations in the brain [12][13][14]. Hippocampus, a structure critical to cognitive processes, has been shown to undergo apoptotic cell death when subjected to hyperglycemic insult [15][16][17].…”