Research is increasingly revealing new roles for microglia in the developed brain beyond their well-known function in protecting it from pathogens and injury. 1,2 For example, recent work has demonstrated microglia are likely to be important for memory processing and executive function. [3][4][5][6] Microglial activity directed at pruning of synapses mediates memory degradation in a complement-dependent manner in a contextual fear conditioning task. 3 Likewise, spatial learning is impaired in animals that are unable to reduce their CA1 microglial density during task acquisition 7 and recognition memory is improved when microglia repopulate the brain after depletion. 8 Roles for microglia have also emerged for regulation of feeding and satiety, 9 and in modifying pain responses. 10,11

Background: Production of inflammatory mediators by reactive microglial cells in the brain is generally considered the primary mechanism underlying the development of symptoms of sickness in response to systemic inflammation. Methods: Depletion of microglia was achieved in C57BL/6 mice by chronic oral administration of PLX5622, a specific antagonist of colony stimulating factor-1 receptor, and in rats by a knock-in model in which the diphtheria toxin receptor was expressed under the control of the endogenous fractalkine receptor (CX3CR1) promoter sequence. After successful microglia depletion, mice and rats were injected with a sickness-inducing dose of lipopolysaccharide according to a 2 (depletion vs. control) × 2 (LPS vs. saline) factorial design. Sickness was measured by body weight loss and decreased locomotor activity in rats and mice, and reduced voluntary wheel running in mice. Results: Chronic administration of PLX5622 in mice and administration of diphtheria toxin to knock-in rats depleted microglia and peripheral tissue macrophages. However, it did not abrogate the inducible expression of proinflammatory cytokines in the brain in response to LPS and even exacerbated it for some of the cytokines. In accordance with these neuroimmune effects, LPS-induced sickness was not abrogated, rather it was exacerbated when measured by running wheel activity in mice. Conclusions: These findings reveal that the sickness-inducing effects of acute inflammation can develop independently of microglia activation.

BackgroundEffective fetal growth requires adequate maternal nutrition coupled to active transport of nutrients across the placenta, which, in turn requires ATP. Epidemiological and experimental evidence has shown that impaired maternal nutrition in utero results in an adverse postnatal phenotype for the offspring. Placental mitochondrial function might link maternal food intake to fetal growth since impaired placental ATP production, in response to poor maternal nutrition, could be a pathway linking maternal food intake to reduced fetal growth.MethodWe assessed the effects of maternal diet on placental water content, ATP levels and mitochondrial DNA (mtDNA) content in mice at embryonic (E) day 18 (E18). Females maintained on either low- (LPD) or normal- (NPD) protein diets were mated with NPD males.ResultsTo investigate the possibility of an underlying mitochondrial stress response, we studied cultured human trophoblast cells (BeWos). High throughput imaging showed that amino acid starvation induces changes in mitochondrial morphology that suggest stress-induced mitochondrial hyperfusion. This is a defensive response, believed to increase mitochondrial efficiency, that could underlie the increase in ATP observed in placenta.ConclusionsThese findings reinforce the pathophysiological links between maternal diet and conceptus mitochondria, potentially contributing to metabolic programming. The quiet embryo hypothesis proposes that pre-implantation embryo survival is best served by a relatively low level of metabolism. This may extend to post-implantation trophoblast responses to nutrition.

Background Families with a child who died of severe, maternally inherited mitochondrial DNA (mtDNA) disease need information on recurrence risk. Estimating this risk is difficult because of (a) heteroplasmydthe coexistence of mutant and normal mtDNA in the same persondand (b) the so-called mitochondrial bottleneck, whereby the small number of mtDNAs that become the founders for the offspring cause variation in dose of mutant mtDNA. The timing of the bottleneck and of segregation of mtDNA during foetal life determines the management options. Therefore, mtDNA heteroplasmy was studied in oocytes and placenta of women in affected families.

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